Stable Anti-OSMR Antibody Formulation

ABSTRACT

The present invention provides, among other things, stable formulations comprising an anti-oncostatin M receptor (OSMR) antibody and having a pH ranging from approximately 6.0-7.6, wherein less than approximately 5% of the anti-OSMR antibody exists as high molecular weight (HMW) species in the formulation.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/179,219, filed on Nov. 2, 2018, which is a continuation of U.S.patent application Ser. No. 15/950,974, filed Apr. 11, 2018, whichclaims priority to U.S. Provisional Applications Ser. No. 62/484,260,filed Apr. 11, 2017, and Ser. No. 62/524,927, filed Jun. 26, 2017, thedisclosures of which are hereby incorporated by reference in theirentirety.

SEQUENCE LISTING

The present specification makes reference to a Sequence Listing(submitted electronically as a .txt file named “KPL-002US3_ST25.txt” onNov. 11, 2019). The .txt file was generated Nov. 8, 2019 and is 18,000bytes in size. The entire contents of the Sequence Listing are hereinincorporated by reference.

BACKGROUND

Developments in biotechnology have made it possible to produce a largevariety of monoclonal antibodies for pharmaceutical applications.Because antibodies are larger and more complex than traditional organicand inorganic drugs, the formulation of such proteins poses specialproblems. One of the problems is the elevated viscosity values ofantibody formulations, especially at high protein concentrations.Another problem is maintaining stability in antibody formulations, whichis a critical concern for regulatory agencies. The delivery of highprotein concentration is often required for subcutaneous administrationdue to volume limitations and dose requirements. Subcutaneousadministration is an attractive route of delivery because it is lessinvasive for patients and reduces inconvenience and discomfort for them.Proteins tend to form viscous solutions at high concentration because oftheir macromolecular nature and potential for intermolecularinteractions. Therefore, there is a need to develop stable antibodyformulations as well as highly concentrated antibody formulations withviscosities at levels that facilitate the manufacture, preparation andadministration of the antibody.

SUMMARY OF THE INVENTION

The present invention provides, among other thing, stable formulationsfor delivery of anti-oncostatin M receptor (OSMR) antibodies. In oneaspect, the present invention provides stable formulations comprising ananti-oncostatin M receptor (OSMR) antibody and having a pH ranging fromapproximately 5.0-7.6, wherein less than approximately 5% of theanti-OSMR antibody exists as high molecular weight (HMW) species in theformulation. In one embodiment, the formulation of the invention is astable, injectable formulation of an anti-oncostatin M receptor (OSMR)antibody, comprising: 75-250 mg/mL of the OSMR monoclonal antibody,10-150 mM L-histidine, 10-150 mM L-Arginine Hydrochloride, 25-150 mMsodium chloride, 0.005%-0.5% (w/v) polysorbate 80 (PS80) at a pH6.6-6.8; wherein the solution is isotonic, with an osmolarity rangingfrom 250-350 mOsm, and wherein at least 90% of the protein exist asstable intact monomeric IgG at about −70° C. or at about 5° C. for atleast 1 month.

In one embodiment, less than 5%, 4%, 3%, 2%, 1%, or 0.5% of theanti-OSMR antibody exists as HMW species in the formulation. In oneembodiment, the amount of HMW species in the formulation increases lessthan 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25° C. for more than 2weeks. In one embodiment, upon storage at 25° C. for 4 weeks, the amountof HMW species in the formulation increases approximately between 0.3%to 0.7%, approximately between 0.3% to 0.6%, or approximately between0.3% to 0.5%. In one embodiment, at least 90%, 92%, 94%, 95%, 96%, 97%,98%, or 99% of the anti-OSMR antibody exists as monomer in the stableformulation. In one embodiment, the amount of monomer decreases lessthan 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at −70° C.for about 3 months, while greater than 90%, greater than 91%, greaterthan 92%, greater than 93%, greater than 94%, greater than 95%, greaterthan 96%, greater than 97%, greater than 98% or greater than 99% of thedrug product exist as intact IgG monomer. In one embodiment, theantibody exhibits at least 95%, 96%, 97%, 98%, 99% or 100% antigenbinding activity after storing at −70° C. for about 3 months. In oneembodiment, the HMW species (% aggregates) do not increase more than 1%,or more than 1.5%, or more than 1.6%, or more than 1.7%, or more than1.8%, or more than 1.9%, or more than 2%, or more than 3%, or more than4%, or more than 5%, upon storage at −70° C. for about 3 months. In oneembodiment, the amount of monomer decreases less than 10%, 8%, 6%, 5%,4%, 3%, 2%, 1%, or 0.5% upon storage at 2-5° C. for about 3 months,while greater than 90%, greater than 91%, greater than 92%, greater than93%, greater than 94%, greater than 95%, greater than 96%, greater than97%, greater than 98% or greater than 99% of the drug product exist asintact IgG monomer. In one embodiment, the antibody exhibits at least95%, 96%, 97%, 98%, 99% or 100% antigen binding activity after storingat 2-5° C. for about 3 months. In one embodiment, the HMW species (%agregates) do not increase more than 1%, or more than 1.5%, or more than1.6%, or more than 1.7%, or more than 1.8%, or more than 1.9%, or morethan 2%, or more than 3%, or more than 4%, or more than 5%, upon storageat 2-5° C. for about 3 months. In one embodiment, the HMW species,and/or the monomer are determined by size exclusion chromatography(SEC), analytical ultracentrifugation (AUC), field flow fractionation(FFF) or light scattering.

In one embodiment, the pH of the formulation ranges betweenapproximately 5.0 to 7.6, between approximately 5.5 to 7.4, betweenapproximately 5.8 to 7.2, between approximately 6.0 to 7.0, betweenapproximately 6.1 to 7.1, between approximately 6.0 to 6.8, betweenapproximately 6.0 to 6.6, between approximately 6.0 to 6.4, betweenapproximately 6.4 to 7.6, between approximately 6.6 to 7.6, betweenapproximately 6.8 to 7.6, between approximately 7.0 to 7.6, betweenapproximately 6.6 to 6.8, between approximately 6.5 to 6.9, betweenapproximately 6.4 to 6.9, or between approximately 7.2 to 7.6. In oneembodiment, the pH of the formulation is approximately 6.2, 6.4, 6.5,6.6, 6.7, 6.8, 6.9, 7.0, 7.2 7.4 or 7.6.

In one embodiment, the anti-OSMR antibody is present at a concentrationof at least approximately 50 mg/mL. In one embodiment, the anti-OSMRantibody is present at a concentration of at least approximately 50mg/mL, 75 mg/mL, 80 mg/mL, 85 mg/mL, 90 mg/mL, 100 mg/mL, 105 mg/mL, 110mg/mL, 120 mg/mL, 125 mg/mL, 130 mg/mL, 135 mg/mL, 140 mg/mL, 145 mg/mL,150 mg/mL, 155 mg/mL, 160 mg/mL, 170 mg/mL, 175 mg/mL, 180 mg/mL, 185mg/mL, 190 mg/mL, 195 mg/mL, 200 mg/mL, 205 mg/mL, 210 mg/mL, 225 mg/mL,or 250 mg/mL.

In one embodiment, the anti-OSMR antibody has a pI ranging from 6.5-8.5.In one embodiment, the anti-OSMR antibody has a pI ranging from 7.0-8.0.In one embodiment, the anti-OSMR comprises one or more charged species,wherein the pI of the charged species ranges from 6.5-8.5. In oneembodiment, the pI is determined by isoelectric focusing (IEF) or ionexchange chromatography (IEX).

In one embodiment, the formulation comprises one or more amino acids. Inone embodiment, the one or more amino acids are present at aconcentration between between 5 mM and 35 mM, between 10 mM and 35 mM,between 15 mM and 30 mM, 1 mM and 250 mM, between 10 mM and 250 mM,between 10 mM and 200 mM, between 10 mM and 150 mM or between 20 mM and150 mM. In one embodiment, the one or more amino acids are selected fromthe group consisting of arginine, glutamic acid, glycine, histidine andcombinations thereof. In one embodiment, the one or more amino acidscomprise arginine. In one embodiment, arginine is selected from thegroup consisting of D-arginine and L-arginine, or combinations thereof.In one embodiment, the one or more amino acids do not include glutamicacid. In one embodiment, the amino acid is L-arginine. In oneembodiment, arginine is present at a concentration between 20 mM and 30mM, 15 mM and 35 mM, 10 mM and 250 mM, between 10 mM and 200 mM, between10 mM and 150 mM, between 10 mM and 125 mM, between 10 mM and 100 mM,between 10 mM and 75 mM, between 10 mM and 50 mM, or between 25 mM and150 mM. In one embodiment, arginine is present at a concentration of 25mM. In one embodiment, the one or more amino acids comprise glutamicacid. In one embodiment, the one or more amino acids comprise arginineand glutamic acid. In one embodiment, the molar ratio of arginine toglutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In oneembodiment, glutamic acid is present at a concentration between 10 mMand 250 mM, between 10 mM and 200 mM, between 10 mM and 150 mM, between10 mM and 125 mM, between 10 mM and 100 mM, between 10 mM and 75 mM,between 10 mM and 50 mM, or between 50 mM and 150 mM. In one embodiment,the one or more amino acids comprise histidine. In one embodiment, theamino acid is L-histidine. In one embodiment, the histidine is presentat a concentration between 10 mM and 20 mM, between 15 mM and 25 mM,between 10 mM and 30 mM, between 5 mM and 25 mM, between 5 mM and 50 mM,between 5 mM and 75 mM, between 5 mM and 100 mM, between 5 mM and 125mM, or between 5 mM and 150 mM. In one embodiment, histidine is presentat concentration of 20 mM. In one embodiment, the one or more aminoacids comprise glycine. In one embodiment, the glycine is present at aconcentration between 10 mM and 250 mM, between 10 mM and 200 mM,between 10 mM and 150 mM, between 10 mM and 125 mM, between 10 mM and100 mM, between 10 mM and 75 mM, between 10 mM and 50 mM, or between 150mM and 200 mM.

In one embodiment, the formulation further comprises a buffer. In oneembodiment, the buffer is selected from the group consisting of citrate,phosphate, succinate, histidine, and combinations thereof. In oneembodiment, the buffer is phosphate. In one embodiment, the buffer ispresent at a concentration between 1 mM and 100 mM, between 5 mM and 75mM, between 5 mM and 50 mM, between 5 mM and 40 mM, between 5 mM and 30mM, between 5 mM and 25 mM, or between 10 mM to 20 mM.

In one embodiment, the formulation further comprises a salt. In oneembodiment, the salt comprises a halide. In one embodiment, the halideis an alkali metal halide. In one embodiment, the salt is NaCl. In oneembodiment, NaCl is present at a concentration between 25 mM and 250 mM,between 25 mM and 200 mM, between 25 mM and 175 mM, between 50 mM and200 mM, between 50 mM and 175 mM, between 50 mM and 150 mM, between 120mM and 130 mM, between 125 mM and 135 mM or between 75 mM and 150 mM. Inone embodiment, NaCl is present at a concentration of 125 mM. In oneembodiment, the molar ratio of NaCl to arginine is at least 1:1, 1.5:1,3:1, or 5:1. In one embodiment, the molar ratio of NaCl to arginine isapproximately 5:1. In another embodiment, the molar ratio of NaCl tohistidine is approximately 6:1.

In another aspect, the present invention provides stable formulationscomprising an anti-oncostatin M receptor (OSMR) antibody at aconcentration of at least 50 mg/mL, at least 100 mg/mL, or at least 150mg/mL, and, in each case, having a pH ranging from approximately6.0-7.6, wherein the anti-OSMR antibody has a pI ranging fromapproximately 6.5-8.5. In one embodiment, the pH of the formulationranges between approximately 6.0 to 7.6, between approximately 6.0 to7.4, between approximately 6.0 to 7.2, between approximately 6.0 to 7.0,between approximately 6.5 to 7.1, between approximately 6.0 to 6.8,between approximately 6.0 to 6.6, between approximately 6.0 to 6.4,between approximately 6.4 to 7.6, between approximately 6.6 to 7.6,between approximately 6.8 to 7.6, between approximately 7.0 to 7.6, orbetween approximately 7.2 to 7.6. In one embodiment, the anti-OSMRantibody is present at a concentration of at least 150 mg/mL, having apH ranging from approximately 6.6 to 6.8 and a pI ranging fromapproximately 7.2 to 8.0.

In one embodiment, the anti-OSMR antibody is present at a concentrationof at least approximately 75 mg/mL, 100 mg/mL, 125 mg/mL, 150 mg/mL, 175mg/mL, 200 mg/mL, 225 mg/mL, or 250 mg/mL. In one embodiment, theanti-OSMR antibody is present at a concentration between approximately50 mg/mL and 250 mg/mL, between approximately 75 mg/mL and 250 mg/mL,between approximately 100 mg/mL and 250 mg/mL, between approximately 125mg/mL and 250 mg/mL, between approximately 150 mg/mL and 250 mg/mL,between approximately 175 mg/mL and 250 mg/mL, between approximately 50mg/mL and 225 mg/mL, between approximately 50 mg/mL and 200 mg/mL,between approximately 50 mg/mL and 175 mg/mL, between approximately 50mg/mL and 150 mg/mL, between approximately 50 mg/mL and 125 mg/mL,between approximately 50 mg/mL and 100 mg/mL, between approximately 150mg/mL and 230 mg/mL, or between approximately 150 mg/mL and 250 mg/mL.

In one embodiment, the anti-OSMR antibody has a pI ranging from 6.5-8.5,7.2-8.0 or from 7.0-8.0.

In one embodiment, the formulation comprises salt. In one embodiment,the salt comprises a halide. In one embodiment, the halide is an alkalimetal halide. In one embodiment, the salt is NaCl. In one embodiment,NaCl is present at a concentration between 25 mM and 250 mM, between 25mM and 200 mM, between 25 mM and 175 mM, between 50 mM and 200 mM,between 50 mM and 175 mM, between 50 mM and 150 mM, between 120 mM and130 mM, between 125 mM and 135 mM or between 75 mM and 150 mM.

In one embodiment, the formulation comprises one or more amino acids. Inone embodiment, the one or more amino acids are present at aconcentration between 5 mM and 35 mM, between 10 mM and 35 mM, between15 mM and 30 mM, between 1 mM and 250 mM, between 10 mM and 250 mM,between 10 mM and 200 mM, between 10 mM and 150 mM or between 20 mM and150 mM. In one embodiment, the one or more amino acids are selected fromthe group consisting of arginine, glutamic acid, glycine, histidine andcombinations thereof. In one embodiment, the one or more amino acidscomprise arginine. In one embodiment, the one or more amino acids do notinclude glutamic acid. In one embodiment, arginine is present at aconcentration between 10 mM and 250 mM, between 10 mM and 200 mM,between 10 mM and 150 mM, between 10 mM and 125 mM, between 10 mM and100 mM, between 10 mM and 75 mM, between 10 mM and 50 mM, or between 25mM and 150 mM. In one embodiment, the one or more amino acids compriseglutamic acid. In one embodiment, the one or more amino acids comprisearginine and glutamic acid. In one embodiment, the molar ratio ofarginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1.In one embodiment, glutamic acid is present at a concentration between10 mM and 250 mM, between 10 mM and 200 mM, between 10 mM and 150 mM,between 10 mM and 125 mM, between 10 mM and 100 mM, between 10 mM and 75mM, between 10 mM and 50 mM, or between 50 mM and 150 mM. In oneembodiment, the molar ratio of NaCl to arginine is at least 1:1, 1.5:1,3:1, or 5:1. In one embodiment, the one or more amino acids comprisehistidine. In one embodiment, the histidine is present at aconcentration between 10 mM and 20 mM, between 5 mM and 25 mM, between 5mM and 50 mM, between 5 mM and 75 mM, between 5 mM and 100 mM, between 5mM and 125 mM, or between 5 mM and 150 mM. In one embodiment, the one ormore amino acids comprise glycine. In one embodiment, the glycine ispresent at a concentration between 10 mM and 250 mM, between 10 mM and200 mM, between 10 mM and 150 mM, between 10 mM and 125 mM, between 10mM and 100 mM, between 10 mM and 75 mM, between 10 mM and 50 mM, orbetween 150 mM and 200 mM.

In one embodiment, the formulation further comprises a buffer. In oneembodiment, the buffer is selected from the group consisting of citrate,phosphate, succinate, histidine and combinations thereof. In oneembodiment, the buffer is phosphate. In one embodiment, the buffer ispresent at a concentration between 1 mM and 100 mM, between 5 mM and 75mM, between 5 mM and 50 mM, between 5 mM and 40 mM, between 5 mM and 30mM, between 5 mM and 25 mM, or between 10 mM to 20 mM. In oneembodiment, the anti-OSMR antibody is present in a stable, injectableformulation, comprising: 50-250 mg/mL of the OSMR monoclonal antibody,10-150 mM L-histidine, 10-150 mM L-Arginine Hydrochloride, 25-150 mMsodium chloride, 0.005%-0.5% (w/v) polysorbate 80 (PS80) at a pH6.6-6.8. The stable, injectable formulation comprises an isotonicsolution. In some embodiments, the formulation buffer comprises 20 mML-Histidine, 25 mM L-Arginine-HCl, 125 mM NaCl, 0.05% (w/v) PS80, pH6.6-6.8. In one embodiment, 75-250 mg/mL anti-OSMR antibody is presentin a stable, injectable formulation comprising 20 mM L-Histidine, 25 mML-Arginine-HCl, 125 mM NaCl, 0.05% (w/v) PS80, pH 6.6-6.8. In oneembodiment, the injectable formulation comprises an osmolarity rangingbetween 250 and 350 mOsm. In one embodiment, the osmolarity of theformulation is between 270 and 300 mOsm. The stable formulationcomprising the anti-OSMR antibody has a pI ranging from 6.5-8.5. In oneembodiment, the stable formulation comprising the anti-OSMR antibody hasa pI ranging from 7.0 to 8.0. In one embodiment, the stable formulationcomprising the anti-OSMR antibody has a pI ranging from 7.2 to 8.0. Inone embodiment, the stable formulation comprising the anti-OSMR antibodycomprises one or more charged species, wherein the pI of the chargedspecies ranges from 6.5 to 8.5.

In one embodiment, the formulation has a viscosity of less than 50 mPa*smeasured by a microfluidic rheometer. In one embodiment, the formulationhas a viscosity of less than 30 mPa*s measured by a microfluidicrheometer. In one embodiment, the formulation has a viscosity of lessthan 20 mPa*s measured by a microfluidic rheometer. In one embodiment,the formulation has a viscosity of less than 15 mPa*s measured by amicrofluidic rheometer. In one embodiment, the formulation has aviscosity, as measured by a microfluidic rheometer, betweenapproximately 1 and 30 mPa*s, between approximately 2 and 28 mPa*s,between approximately 4 and 30 mPa*s, between approximately 6 and 30mPa*s, between approximately 8 and 30 mPa*s, between approximately 10and 30 mPa*s, between approximately 12 and 30 mPa*s, betweenapproximately 14 and 30 mPa*s, between approximately 16 and 30 mPa*s,between approximately 18 and 30 mPa*s, between approximately 20 and 30mPa*s, between approximately 22 and 30 mPa*s, between approximately 24and 30 mPa*s, between approximately 26 and 30 mPa*s, or betweenapproximately 28 and 30 mPa*s. In one embodiment, the formulation has ashear rate of less than 1000 s⁻¹ at 25° C.

In one embodiment, the formulation is a liquid formulation. In oneembodiment, the formulation is reconstituted from a lyophilized powder.

In one embodiment, the formulation can be expelled via a 27G ½″ needlewith 6.5 pound-force or less at an injection rate of 0.1 mL/second atabout 25° C. In one embodiment, the formulation is easily injectable.

In one embodiment, the anti-OSMR antibody comprises a light chaincomplementary-determining region 1 (LCDR1) defined by SEQ ID NO: 8, alight chain complementary-determining region 2 (LCDR2) defined by SEQ IDNO: 9, and a light chain complementary-determining region 3 (LCDR3)defined by SEQ ID NO: 10; and a heavy chain complementary-determiningregion 1 (HCDR1) defined by SEQ ID NO: 5, a heavy chaincomplementary-determining region 2 (HCDR2) defined by SEQ ID NO: 6, anda heavy chain complementary-determining region 3 (HCDR3) defined by SEQID NO: 7. In one embodiment, the anti-OSMR antibody comprises a lightchain variable domain having an amino acid sequence at least 90%identical to SEQ ID NO: 4 a heavy chain variable domain having an aminoacid sequence at least 90% identical to SEQ ID NO: 3. In one embodiment,the light chain variable domain has the amino acid sequence set forth inSEQ ID NO: 4 and the heavy chain variable domain has the amino acidsequence set forth in SEQ ID NO: 3. In one embodiment, the anti-OSMRantibody comprises CH1, hinge and CH2 domains derived from an IgG4antibody fused to a CH3 domain derived from an IgG1 antibody. In oneembodiment, the anti-OSMR antibody comprises a light chain having anamino acid sequence at least 90% identical to SEQ ID NO: 2 and a heavychain having an amino acid sequence at least 90% identical to SEQ IDNO: 1. In one embodiment, the light chain has the amino acid sequenceset forth in SEQ ID NO: 2 and the heavy chain has the amino acidsequence set forth in SEQ ID NO: 1.

In another aspect, the present invention provides stable formulationscomprising an antibody at a concentration of at least 50 mg/mL andarginine, wherein the arginine is present at an amount greater than anynon-arginine amino acid in the formulation. In one embodiment, theformulation does not comprise glutamic acid. In one embodiment, theformulation comprises glutamic acid. In one embodiment, the molar ratioof arginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or1:1. In one embodiment, the amino acid is L-arginine.

In one embodiment, the formulation of the anti-OSMR antibody comprisinga light chain having an amino acid sequence at least 90% identical toSEQ ID NO: 2 and a heavy chain having an amino acid sequence at least90% identical to SEQ ID NO: 1 comprises 20 mM L-Histidine, 25 mML-Arginine-HCl, 125 mM NaCl, 0.05% (w/v) PS80, pH 6.6-6.8. In oneembodiment, the formulation of the anti-OSMR antibody comprising a lightchain variable domain having an amino acid sequence at least 90%identical to SEQ ID NO: 4 a heavy chain variable domain having an aminoacid sequence at least 90% identical to SEQ ID NO: 3 comprises 20 mML-Histidine, 25 mM L-Arginine-HCl, 125 mM NaCl, 0.05% (w/v) PS80, pH6.6-6.8. In one embodiment, the formulation of the anti-OSMR antibodycomprising the light chain variable domain having the amino acidsequence set forth in SEQ ID NO: 4 and the heavy chain variable domainhaving the amino acid sequence set forth in SEQ ID NO: 3 comprises 20 mML-Histidine, 25 mM L-Arginine-HCl, 125 mM NaCl, 0.05% (w/v) PS80, pH6.6-6.8. In one embodiment, the formulation of the anti-OSMR antibodycomprising the light chain has the amino acid sequence set forth in SEQID NO: 2 and the heavy chain has the amino acid sequence set forth inSEQ ID NO: 1 comprises 20 mM L-Histidine, 25 mM L-Arginine-HCl, 125 mMNaCl, 0.05% (w/v) PS80, pH 6.6-6.8.

In another aspect, the present invention provides methods of treating adisease, disorder or condition associated with OSMR comprisingadministering into a subject in need of treatment any stable formulationdescribed above. In one embodiment, the formulation is administeredintravenously. In one embodiment, the formulation is administeredsubcutaneously. In one embodiment, the disease, disorder or conditionassociated with OSMR is selected from pruritus, atopic dermatitis,inflammation, pain, prurigo nodularis, dermatitis, asthma, autoimmunedisease, paraneoplastic autoimmune diseases, cartilage inflammation,fibrosis (including, but not limited to, pulmonary fibrosis and skinfibrosis), fibrotic disease, chronic obstructive pulmonary disease(COPD), interstitial pneumonitis, abnormal collagen deposition, systemiccutaneous amyloidosis, primary cutaneous amyloidosis, Behcet's disease,nasal polyposis, liver cirrhosis, cartilage degradation, bonedegradation, arthritis, rheumatoid arthritis, juvenile arthritis,juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoidarthritis, polyarticular juvenile rheumatoid arthritis, systemic onsetjuvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenileenteropathic arthritis, juvenile reactive arthritis, juvenile Reter'sSyndrome, SEA Syndrome (Seronegativity, Enthesopathy, ArthropathySyndrome), juvenile dermatomyositis, juvenile psoriatic arthritis,juvenile scleroderma, juvenile systemic lupus erythematosus, juvenilevasculitis, pauciarticular rheumatoid arthritis, polyarticularrheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosingspondylitis, enteropathic arthritis, reactive arthritis, Reter'sSyndrome, SEA Syndrome (Seronegativity, Enthesopathy, ArthropathySyndrome), dermatomyositis, psoriatic arthritis, scleroderma,scleroderma-associated interstitial lung disease, vasculitis, myolitis,polymyolitis, dermatomyolitis, polyarteritis nodossa, Wegener'sgranulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis,scleroderma, sclerosis, primary biliary sclerosis, sclerosingcholangitis, Sjogren's syndrome, psoriasis, plaque psoriasis, guttatepsoriasis, inverse psoriasis, pustular psoriasis, erythrodermicpsoriasis, dermatitis, atherosclerosis, lupus, Still's disease, SystemicLupus Erythematosus (SLE), myasthenia gravis, inflammatory bowel disease(IBD), Crohn's disease, ulcerative colitis, celiac disease, multiplesclerosis (MS), asthma, COPD, rhinosinusitis, rhinosinusitis withpolyps, eosinophilic esophagitis, eosinophilic bronchitis, bronchitis,Guillain-Barre disease, Type I diabetes mellitus, thyroiditis (e.g.,Graves' disease), Addison's disease, Reynaud's phenomenon, autoimmunehepatitis, GVHD, transplantation rejection, kidney damage,cardiovascular disease, infection, sepsis, HIV infection, trauma, kidneyallograft nephropathy, IgA nephropathy, diabetic nephropathy, diabeticretinopathy, macular degeneration, biliary atresia, congestive heartfailure, atherosclerosis, restenosis, radiation-induced fibrosis,chemotherapy-induced fibrosis, burns, surgical trauma, andglomerulosclerosis.

In another aspect, the present invention provides methods for treatingpruritus comprising subcutaneously administering to a subject in need oftreatment a formulation comprising an anti-oncostatin M receptor (OSMR)antibody at a concentration of at least 50 mg/mL. In one embodiment, theanti-OSMR antibody is present at a concentration of at leastapproximately 75 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 105 mg/mL, 110mg/mL, 120 mg/mL, 125 mg/mL, 130 mg/mL, 135 mg/mL, 140 mg/mL, 145 mg/mL,150 mg/mL, 155 mg/mL, 160 mg/mL, 170 mg/mL, 175 mg/mL, 180 mg/mL, 185mg/mL, 190 mg/mL, 200 mg/mL, 205 mg/mL, 210 mg/mL, 215 mg/mL, 220 mg/mL,225 mg/mL, or 250 mg/mL. In one embodiment, the anti-OSMR antibody ispresent at a concentration between approximately 50 mg/mL and 250 mg/mL,between approximately 75 mg/mL and 250 mg/mL, between approximately 100mg/mL and 250 mg/mL, between approximately 125 mg/mL and 250 mg/mL,between approximately 150 mg/mL and 250 mg/mL, between approximately 175mg/mL and 250 mg/mL, between approximately 50 mg/mL and 225 mg/mL,between approximately 50 mg/mL and 200 mg/mL, between approximately 50mg/mL and 175 mg/mL, between approximately 50 mg/mL and 150 mg/mL,between approximately 50 mg/mL and 125 mg/mL, or between approximately50 mg/mL and 100 mg/mL, or between approximately 150 mg/mL and 250mg/mL.

In one embodiment, the anti-OSMR antibody comprises a light chaincomplementary-determining region 1 (LCDR1) defined by SEQ ID NO: 8, alight chain complementary-determining region 2 (LCDR2) defined by SEQ IDNO: 9, and a light chain complementary-determining region 3 (LCDR3)defined by SEQ ID NO: 10; and a heavy chain complementary-determiningregion 1 (HCDR1) defined by SEQ ID NO: 5, a heavy chaincomplementary-determining region 2 (HCDR2) defined by SEQ ID NO: 6, anda heavy chain complementary-determining region 3 (HCDR3) defined by SEQID NO: 7. In one embodiment, the anti-OSMR antibody comprises a lightchain variable domain having an amino acid sequence at least 90%identical to SEQ ID NO: 4 and a heavy chain variable domain having anamino acid sequence at least 90% identical to SEQ ID NO: 3. In oneembodiment, the light chain variable domain has the amino acid sequenceset forth in SEQ ID NO: 4 and the heavy chain variable domain has theamino acid sequence set forth in SEQ ID NO: 3. In one embodiment, theanti-OSMR antibody comprises CH1, hinge and CH2 domains derived from anIgG4 antibody fused to a CH3 domain derived from an IgG1 antibody. Inone embodiment, the anti-OSMR antibody comprises a light chain having anamino acid sequence at least 90% identical to SEQ ID NO: 2 and a heavychain having an amino acid sequence at least 90% identical to SEQ IDNO: 1. In one embodiment, the light chain has the amino acid sequenceset forth in SEQ ID NO: 2; and the heavy chain has the amino acidsequence set forth in SEQ ID NO: 1.

In one embodiment, the formulation is administered in a volume of lessthan 5 mL, 4 mL, 3 mL, or 2 mL. In one embodiment, the formulation has aviscosity of less than 50 mPa*s, less than 30 mPa*s, less than 20 mPa*s,or less than 15 mPa*s as measured by a microfluidic rheometer. In oneembodiment, the formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 1 and 30 mPa*s, betweenapproximately 2 and 28 mPa*s, between approximately 4 and 30 mPa*s,between approximately 6 and 30 mPa*s, between approximately 8 and 30mPa, between approximately 10 and 30 mPa*s, between approximately 12 and30 mPa*s, between approximately 14 and 30 mPa*s, between approximately16 and 30 mPa*s, between approximately 18 and 30 mPa*s, betweenapproximately 20 and 30 mPa*s, between approximately 22 and 30 mPa*s,between approximately 24 and 30 mPa*s, between approximately 26 and 30mPa*s, or between approximately 28 and 30 mPa*s. In one embodiment, theformulation has a shear rate of less than 1000 s⁻¹ at 25° C.

In one embodiment, less than 5%, 4%, 3%, 2%, 1%, or 0.5% of theanti-OSMR antibody exists as HMW species in the formulation. In oneembodiment, the amount of HMW species in the formulation increases lessthan 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25° C. for 2 weeks ormore. In one embodiment, the amount of HMW species in the formulationincreases less than 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25° C.for 4 weeks or more. In one embodiment, the amount of HMW species in theformulation increases less than 5%, 4%, 3%, 2%, 1%, or 0.5% upon storageat 25° C. for 3 months or more. In one embodiment, upon storage at 25°C. for 4 weeks, the amount of HMW species in the formulation increasesapproximately between 0.3% and 0.7%, approximately between 0.3% and0.6%, or approximately between 0.3% and 0.5%. In one embodiment, theformulation is stable upon storage at about 25° C. for 3 months, and theamount of HMW species in the formulation increases approximately between0.3% to 5%, approximately between 0.3% to 3%, or approximately between0.3% to 2.5%. In one embodiment, the formulation is stable upon storageat about 25° C. for 3 months, and the percent of intact IgG monomer isabove 90% of the total protein content.

In one embodiment, the formulation is stable through multiplefreeze-thaw cycles. In one embodiment, the formulation is stable instorage at about 25° C. the amount of intact IgG is above 90% aftermultiple freeze-thaw cycles and storage for at least 3 months, or atleast 6 months or at least 12 months or at least 24 months. In oneembodiment, the formulation is stable in storage at 2-5° C. for at least3 months, or for at least 6 months, or for at least 1 year, or for atleast 2 years, or for at least 3 years, or for at least 4 years, or forat least 5 years, or, for at least 10 years. In one embodiment, theformulation is stable in storage at −70° C. for at least 3 months, forat least 6 months, for at least 1 year, for at least 2 years, for atleast 3 years, for at least 4 years, for at least 5 years, or, for atleast 10 years.

BRIEF DESCRIPTION OF THE DRAWING

The drawings are for illustration purposes only not for limitation.

FIG. 1 depicts an exemplary graph illustrating the effect of proteinconcentration on viscosity in two different formulations of anti-OSMRantibody.

FIG. 2 depicts plot of viscosity over temperature of the formulation at209 mg/mL and 180 mg/mL.

FIG. 3 depicts an exemplary chromatogram showing HMW species in a samplethat was stressed by storage at 40° C.

FIG. 4 depicts an exemplary graph showing predicted vs. measured monomercontent. A partial least squares regression was performed to modelmonomer content in samples after two weeks at 40° C.

FIG. 5 depicts an exemplary graph showing predicted vs. measuredcapillary isoelectric focusing (cIEF) difference in main peakpercentage. A partial least squares regression was performed to modelcIEF difference in main peak percentage data from Round 1 in samplesafter two weeks at 40° C.

FIG. 6 depicts an exemplary graph showing predicted vs. measured cIEFdifference in main peak percentage. A partial least squares regressionwas performed to model cIEF difference in main peak percentage data fromRound 1 in samples after four weeks at 25° C.

FIG. 7 depicts exemplary correlation coefficients for various Round 1formulation variables at t2 (samples were stored for two weeks at 40°C.) and t4 (samples were stored for four weeks at 25° C.).

FIG. 8 depicts characteristics of the exemplary formulation samples whenstored over a period of three months at −70° C. and at 5° C.

FIG. 9 depicts characteristics of the exemplary formulation samples whenstored over a period of three months at 25±2° C. (acceleratedconditions) and at 40±2° C. (stressed) conditions.

DEFINITIONS

In order for the present invention to be more readily understood,certain terms are first defined below. Additional definitions for thefollowing terms and other terms are set forth throughout thespecification. The publications and other reference materials referencedherein to describe the background of the invention and to provideadditional detail regarding its practice are hereby incorporated byreference.

Amino acid: As used herein, term “amino acid,” in its broadest sense,refers to any compound and/or substance that can be incorporated into apolypeptide chain. In some embodiments, an amino acid has the generalstructure H₂N—C(H)(R)—COHO. In some embodiments, an amino acid is anaturally occurring amino acid. In some embodiments, an amino acid is asynthetic amino acid; in some embodiments, an amino acid is a d-aminoacid; in some embodiments, an amino acid is an 1-amino acid. “Standardamino acid” refers to any of the twenty standard 1-amino acids commonlyfound in naturally occurring peptides. “Nonstandard amino acid” refersto any amino acid, other than the standard amino acids, regardless ofwhether it is prepared synthetically or obtained from a natural source.As used herein, “synthetic amino acid” encompasses chemically modifiedamino acids, including but not limited to salts, amino acid derivatives(such as amides), and/or substitutions. Amino acids, including carboxyl-and/or amino-terminal amino acids in peptides, can be modified bymethylation, amidation, acetylation, protecting groups, and/orsubstitution with other chemical groups that can change the peptide'scirculating half-life without adversely affecting their activity. Aminoacids may participate in a disulfide bond. Amino acids may comprise oneor posttranslational modifications, such as association with one or morechemical entities (e.g., methyl groups, acetate groups, acetyl groups,phosphate groups, formyl moieties, isoprenoid groups, sulfate groups,polyethylene glycol moieties, lipid moieties, carbohydrate moieties,biotin moieties, etc.). The term “amino acid” is used interchangeablywith “amino acid residue,” and may refer to a free amino acid and/or toan amino acid residue of a peptide. It will be apparent from the contextin which the term is used whether it refers to a free amino acid or aresidue of a peptide.

Amelioration: As used herein, the term “amelioration” is meant theprevention, reduction or palliation of a state, or improvement of thestate of a subject. Amelioration includes, but does not require completerecovery or complete prevention of a disease condition. In someembodiments, amelioration includes increasing levels of relevant proteinor its activity that is deficient in relevant disease tissues.

Approximately or about: As used herein, the term “approximately” or“about,” as applied to one or more values of interest, refers to a valuethat is similar to a stated reference value. In certain embodiments, theterm “approximately” or “about” refers to a range of values that fallwithin 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greaterthan or less than) of the stated reference value unless otherwise statedor otherwise evident from the context (except where such number wouldexceed 100% of a possible value).

Biologically active: As used herein, the phrase “biologically active”refers to a characteristic of any agent that has activity in abiological system, and particularly in an organism. For instance, anagent that, when administered to an organism, has a biological effect onthat organism, is considered to be biologically active. In particularembodiments, where a protein or polypeptide is biologically active, aportion of that protein or polypeptide that shares at least onebiological activity of the protein or polypeptide is typically referredto as a “biologically active” portion.

Diluent: As used herein, the term “diluent” refers to a pharmaceuticallyacceptable (e.g., safe and non-toxic for administration to a human)diluting substance useful for the preparation of a reconstitutedformulation. Exemplary diluents include sterile water, bacteriostaticwater for injection (BWFI), a pH buffered solution (e.g.phosphate-buffered saline), sterile saline solution, Ringer's solutionor dextrose solution.

Delivery: As used herein, the term “delivery” encompasses both local andsystemic delivery.

Half-life: As used herein, the term “half-life” is the time required fora quantity such as nucleic acid or protein concentration or activity tofall to half of its value as measured at the beginning of a time period.

Improve, increase, or reduce: As used herein, the terms “improve,”“increase” or “reduce,” or grammatical equivalents, indicate values thatare relative to a baseline measurement, such as a measurement in thesame individual prior to initiation of the treatment described herein,or a measurement in a control subject (or multiple control subject) inthe absence of the treatment described herein. A “control subject” is asubject afflicted with the same form of disease as the subject beingtreated, who is about the same age as the subject being treated.

Stability: As used herein, the term “stable” refers to the ability ofthe therapeutic agent (e.g., a recombinant enzyme) to maintain itstherapeutic efficacy (e.g., all or the majority of its intendedbiological activity and/or physiochemical integrity) over extendedperiods of time. The stability of a therapeutic agent, and thecapability of the pharmaceutical composition to maintain stability ofsuch therapeutic agent, may be assessed over extended periods of time(e.g., for at least 1, 3, 6, 12, 18, 24, 30, 36 months or more). Ingeneral, pharmaceutical compositions described herein have beenformulated such that they are capable of stabilizing, or alternativelyslowing or preventing the degradation, of one or more therapeutic agentsformulated therewith (e.g., recombinant proteins). In the context of aformulation a stable formulation is one in which the therapeutic agenttherein essentially retains its physical and/or chemical integrity andbiological activity upon storage and during processes (such asfreeze/thaw, mechanical mixing and lyophilization). For proteinstability, it can be measure by formation of high molecular weight (HMW)aggregates, loss of enzyme activity, generation of peptide fragments andshift of charge profiles. For the purpose of the present application,the term high molecular weight species (HMW) of the product and“aggregates” are used interchangeably.

Substantial identity: The phrase “substantial identity” is used hereinto refer to a comparison between amino acid or nucleic acid sequences.As will be appreciated by those of ordinary skill in the art, twosequences are generally considered to be “substantially identical” ifthey contain identical residues in corresponding positions. As is wellknown in this art, amino acid or nucleic acid sequences may be comparedusing any of a variety of algorithms, including those available incommercial computer programs such as BLAS TN for nucleotide sequencesand BLASTP, gapped BLAST, and PSI-BLAST for amino acid sequences.Exemplary such programs are described in Altschul, et al., Basic localalignment search tool, J Mal. Biol., 215(3): 403-410, 1990; Altschul, etal., Methods in Enzymology; Altschul et al., Nucleic Acids Res.25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guideto the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al.,(eds.), Bioinformatics Methods and Protocols (Methods in MolecularBiology, Vol. 132), Humana Press, 1999. In addition to identifyingidentical sequences, the programs mentioned above typically provide anindication of the degree of identity. In some embodiments, two sequencesare considered to be substantially identical if at least 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99% or more of their corresponding residues are identical over arelevant stretch of residues. In some embodiments, the relevant stretchis a complete sequence. In some embodiments, the relevant stretch is atleast 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400,425, 450, 475, 500 or more residues.

Suitable for subcutaneous delivery: As used herein, the phrase “suitablefor subcutaneous delivery” or “formulation for subcutaneous delivery” asit relates to the pharmaceutical compositions of the present inventiongenerally refers to the stability, viscosity, and solubility propertiesof such compositions, as well as the ability of such compositions todeliver an effective amount of antibody contained therein to thetargeted site of delivery.

Patient: As used herein, the term “patient” or “subject” refers to anyorganism to which a provided composition may be administered, e.g., forexperimental, diagnostic, prophylactic, cosmetic, and/or therapeuticpurposes. Typical patients include animals (e.g., mammals such as mice,rats, rabbits, non-human primates, and/or humans). In some embodiments,a patient is a human. A human includes pre- and post-natal forms.

Pharmaceutically acceptable: The term “pharmaceutically acceptable” asused herein, refers to substances that, within the scope of soundmedical judgment, are suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

Subject: As used herein, the term “subject” refers to a human or anynon-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine,sheep, horse or primate). A human includes pre- and post-natal forms. Inmany embodiments, a subject is a human being. A subject can be apatient, which refers to a human presenting to a medical provider fordiagnosis or treatment of a disease. The term “subject” is used hereininterchangeably with “individual” or “patient.” A subject can beafflicted with or is susceptible to a disease or disorder but may or maynot display symptoms of the disease or disorder.

Substantially: As used herein, the term “substantially” refers to thequalitative condition of exhibiting total or near-total extent or degreeof a characteristic or property of interest. One of ordinary skill inthe biological arts will understand that biological and chemicalphenomena rarely, if ever, go to completion and/or proceed tocompleteness or achieve or avoid an absolute result. The term“substantially” is therefore used herein to capture the potential lackof completeness inherent in many biological and chemical phenomena.

Systemic distribution or delivery: As used herein, the terms “systemicdistribution,” “systemic delivery,” or grammatical equivalent, refer toa delivery or distribution mechanism or approach that affect the entirebody or an entire organism. Typically, systemic distribution or deliveryis accomplished via body's circulation system, e.g., blood stream.Compared to the definition of “local distribution or delivery.”

Target tissues: As used herein, the term “target tissues” refers to anytissue that is affected by a disease or disorder to be treated. In someembodiments, target tissues include those tissues that displaydisease-associated pathology, symptom, or feature.

Therapeutically effective amount: As used herein, the term“therapeutically effective amount” of a therapeutic agent means anamount that is sufficient, when administered to a subject suffering fromor susceptible to a disease, disorder, and/or condition, to treat,diagnose, prevent, and/or delay the onset of the symptom(s) of thedisease, disorder, and/or condition. It will be appreciated by those ofordinary skill in the art that a therapeutically effective amount istypically administered via a dosing regimen comprising at least one unitdose.

Treating: As used herein, the term “treat,” “treatment,” or “treating”refers to any method used to partially or completely alleviate,ameliorate, relieve, inhibit, prevent, delay onset of, reduce severityof and/or reduce incidence of one or more symptoms or features of aparticular disease, disorder, and/or condition. Treatment may beadministered to a subject who does not exhibit signs of a disease and/orexhibits only early signs of the disease for the purpose of decreasingthe risk of developing pathology associated with the disease.

DETAILED DESCRIPTION

The present invention provides, among other things, stable formulationscomprising an anti-Oncostatin M Receptor 3 (OSMR) antibody and having apH ranging from approximately 6.0-7.6, wherein less than 5% of theanti-OSMR antibody exists as high molecular weight (HMW) species in theformulation. Also provided are stable formulations comprising ananti-OSMR antibody having a pH ranging from approximately 6.0-7.6,wherein the anti-OSMR antibody has a pI ranging from about 6.5-8.5. Insome embodiments, the formulation comprises arginine and, optionally,NaCl. In some embodiments, the formulation is suitable for subcutaneousdelivery. In some embodiments, stable formulations of the presentinvention are suitable for treating pruritus or other diseases anddisorders associated with OSMR.

Various aspects of the invention are described in detail in thefollowing sections. The use of sections is not meant to limit theinvention. Each section can apply to any aspect of the invention. Inthis application, the use of “or” means “and/or” unless statedotherwise.

Anti-Oncostatin M Receptor (OSMR) Antibodies

In some embodiments, inventive compositions and methods provided by thepresent invention are used to deliver an anti-OSMR antibody to a subjectin need. In certain embodiments of the invention, the anti-OSMRantibodies are fully-human monoclonal antibodies that specificallyinhibit IL-31 and oncostatin M (OSM)-induced activation of the IL-31receptor and type II OSM receptor, respectively, through binding toOSMR, the subunit common to both receptors. The antibody is comprised oftwo light chains and two heavy chains. In some embodiments, the lightchain contains a lambda constant region. The constant regions of theheavy chain contain the CH1, hinge, and CH2 domains of a humanimmunoglobulin IgG4 antibody fused to the CH3 domain of a human IgG1antibody. In other embodiments, the heavy chain of the anti-OSMRantibody contains a S228P modification to improve stability and a N297Qmodification to remove an N-linked glycosylation site.

Anti-OSMR Heavy Chain Amino Acid Sequence

(SEQ ID NO: 1) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQATGQGLEWMGWMNPNSGYTGYAQKFQGRVTMTRDTSISTAYMEMSSLRSEDTAVYYCARDIVAANTDYYFYYGMDVWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PG

Anti-OSMR Light Chain Amino Acid Sequence

(SEQ ID NO: 2) QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNTVNWYHQLPGTAPKLLIYNINKRPSGVPDRFSGSKSGSSASLAISGLQSEDEADYYCSTWDDSLDGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGS TVEKTVAPTECS

Anti-OSMR Heavy Chain Variable Domain Amino Acid Sequence

(SEQ ID NO: 3) QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQATGQGLEWMGWMNPNSGYTGYAQKFQGRVTMTRDTSISTAYMEMSSLRSEDTAVYYCARDIVAANTDYYFYYGMDVWGQGTTVTVSS

Anti-OSMR Light Chain Variable Domain Amino Acid Sequence

(SEQ ID NO: 4) QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNTVNWYHQLPGTAPKLLIYNINKRPSGVPDRFSGSKSGSSASLAISGLQSEDEADYYCSTWDDSLDGVVFG GGTKLTVLG

Anti-OSMR Heavy Chain Variable Domain CDR 1 (HCDR1) Amino Acid Sequence

(SEQ ID NO: 5) SYEIN

Anti-OSMR Heavy Chain Variable Domain CDR 2 (HCDR2) Amino Acid Sequence

(SEQ ID NO: 6) WMGWMNPNSGYTGYAQKFQGR

Anti-OSMR Heavy Chain Variable Domain CDR 3 (HCDR3) Amino Acid Sequence

(SEQ ID NO: 7) DIVAANTDYYFYYGMDV

Anti-OSMR Light Chain Variable Domain CDR1 (LCDR1) Amino Acid Sequence

(SEQ ID NO: 8) SGSNSNIGSNTVN

Anti-OSMR Light Chain Variable Domain CDR2 (LCDR2) Amino Acid Sequence

(SEQ ID NO: 9) NINKRPS

Anti-OSMR Light Chain Variable Domain CDR3 (LCDR3) Amino Acid Sequence

(SEQ ID NO: 10) STWDDSLDGVV

Anti-OSMR Heavy Chain Signal Peptide Amino Acid Sequence

(SEQ ID NO: 11) MDFGLSLVFLVLILKGVQC

Anti-OSMR Light Chain Signal Peptide Amino Acid Sequence

(SEQ ID NO: 12) MATGSRTSLLLAFGLLCLSWLQEGSA

Anti-OSMR Heavy Chain Amino Acid Sequence—IgG4 CH1, Hinge, and CH2Domains

(SEQ ID NO: 13) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVS NKGLPSSIEKTISKAK

Anti-OSMR Heavy Chain Amino Acid Sequence—IgG1 CH3 Domain

(SEQ ID NO: 14) GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPG

Anti-OSMR Heavy Chain Amino Acid Sequence—Constant Domain

(SEQ ID NO: 15) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPG

Anti-OSMR Light Chain Amino Acid Sequence—IgG Lambda Constant Domain

(SEQ ID NO: 16) QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPT ECS

In some embodiments of the invention, an anti-OSMR antibody comprises alight chain complementary-determining region 1 (LCDR1) defined by SEQ IDNO: 8, a light chain complementary-determining region 2 (LCDR2) definedby SEQ ID NO: 9, and a light chain complementary-determining region 3(LCDR3) defined by SEQ ID NO: 10; and a heavy chaincomplementary-determining region 1 (HCDR1) defined by SEQ ID NO: 5, aheavy chain complementary-determining region 2 (HCDR2) defined by SEQ IDNO: 6, and a heavy chain complementary-determining region 3 (HCDR3)defined by SEQ ID NO: 7.

In some embodiments of the invention, an anti-OSMR antibody comprisesCDR amino acid sequences with at least 75%, 80%, 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity with one or more ofSEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 5, SEQ ID NO: 6,and SEQ ID NO: 7.

In some embodiments of the invention, an anti-OSMR antibody comprises alight chain variable domain having an amino acid sequence at least 90%identical to SEQ ID NO: 4 and a heavy chain variable domain having anamino acid sequence at least 90% identical to SEQ ID NO: 3. In someembodiments of the invention, an anti-OSMR antibody has a light chainvariable domain amino acid sequence with at least 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% ormore identity to SEQ ID NO: 4 and a heavy chain variable domain aminoacid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ IDNO: 3. In some embodiments of the invention, an anti-OSMR antibodycomprises a light chain variable domain that has the amino acid sequenceset forth in SEQ ID NO: 4 and a heavy chain variable domain that has theamino acid sequence set forth in SEQ ID NO: 3.

In some embodiments of the invention, an anti-OSMR antibody comprises alight chain having an amino acid sequence at least 90% identical to SEQID NO: 2 and a heavy chain having an amino acid sequence at least 90%identical to SEQ ID NO: 1. In some embodiments of the invention, ananti-OSMR antibody has a light chain amino acid sequence with at least50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or more identity to SEQ ID NO: 2 and a heavy chainamino acid sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identityto SEQ ID NO: 1. In some embodiments of the invention, an anti-OSMRantibody comprises a light chain that has the amino acid sequence setforth in SEQ ID NO: 2 and a heavy chain that has the amino acid sequenceset forth in SEQ ID NO: 1.

In some embodiments of the invention, a heavy chain constant region ofan anti-OSMR antibody comprises CH1, hinge and CH2 domains derived froman IgG4 antibody fused to a CH3 domain derived from an IgG1 antibody. Insome embodiments, the CH1, hinge and CH2 domains derived from an IgG4antibody comprise SEQ ID NO: 13. In some embodiments, the CH3 domainderived from an IgG1 antibody comprises SEQ ID NO: 14. In someembodiments, the heavy chain constant region of an anti-OSMR antibodyaccording to the present invention comprises an amino acid sequence withat least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 13. In someembodiments, the heavy chain constant region of an anti-OSMR antibodyaccording to the present invention comprises an amino acid sequence withat least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 14. In someembodiments, the heavy chain constant region of an anti-OSMR antibodyaccording to the present invention comprises an amino acid sequence withat least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 15. In someembodiments, an anti-OSMR antibody according to the present inventioncomprises a lambda constant domain derived from an IgG antibody. In someembodiments, the lambda constant domain derived from an IgG comprisesSEQ ID NO: 16. In some embodiments, an anti-OSMR antibody according tothe present invention comprises an amino acid sequence with at least50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or more identity to SEQ ID NO: 16.

Formulations

Exemplary formulations of the present invention are described herein.Formulations of the present invention comprise anti-OSMR antibodies asdescribed above. In some embodiments, formulations are stableformulations for subcutaneous delivery. Among other things, formulationsdescribed herein are capable of solubilizing high concentrations ofanti-OSMR antibody and are suitable for subcutaneous, intradermal,intramuscular and/or intra-articular delivery.

In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 50mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 60mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 70mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 80mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 90mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 100mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 110mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 120mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 130mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 140mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 150mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 160mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 170mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 180mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 190mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 200mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 210mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 220mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 230mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 240mg/mL. In some embodiments of the invention, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 250mg/mL. In some embodiments, the formulation comprises about 180 mg/mlanti-OSMR antibody.

In some embodiments, the formulation prior to packaging or fillingcomprises about 5% more drug substance than the concentration intendedin the final product formulation (the target concentration). Uponpackaging or filling of the drug product, the formulation comprisingabout 5% more drug substance is diluted to the target concentration withplacebo, i.e., the same formulation buffer, but lacking drug substance(e.g. 20 mM L-Histidine, 25 mM L-Arginine HCl, 125 mM NaCl, 0.05% (w/v)PS80, pH 6.6-6.8)

Amino Acids

In some embodiments of the invention, a formulation comprises one ormore amino acids. In some embodiments, the one or more amino acids arepresent at a concentration between 10 mM and 250 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 10 mM and 225 mM. In some embodiments, the one or more aminoacids are present at a concentration between 10 mM and 200 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 10 mM and 175 mM. In some embodiments, the one or more aminoacids are present at a concentration between 10 mM and 150 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 10 mM and 125 mM. In some embodiments, the one or more aminoacids are present at a concentration between 10 mM and 100 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 10 mM and 75 mM. In some embodiments, the one or more aminoacids are present at a concentration between 10 mM and 50 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 10 mM and 25 mM. In some embodiments, the one or more aminoacids are present at a concentration between 20 mM and 250 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 25 mM and 250 mM. In some embodiments, the one or more aminoacids are present at a concentration between 50 mM and 250 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 75 mM and 250 mM. In some embodiments, the one or more aminoacids are present at a concentration between 100 mM and 250 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 125 mM and 250 mM. In some embodiments, the one or more aminoacids are present at a concentration between 150 mM and 250 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 175 mM and 250 mM. In some embodiments, the one or more aminoacids are present at a concentration between 200 mM and 250 mM. In someembodiments, the one or more amino acids are present at a concentrationbetween 5 mM and 35 mM, between 10 mM and 35 mM, or between 15 mM and 30mM.

In some embodiments of the invention, a formulation comprises one ormore amino acids selected from arginine, glutamic acid, glycine,histidine and combinations thereof. In some embodiments, the formulationcomprises arginine. In some embodiments, the formulation comprisesglutamic acid. In some embodiments, the formulation comprises arginineand glutamic acid. In some embodiments, the formulation compriseshistidine. In some embodiments, the formulation comprises glycine.

In some embodiments, a formulation comprising arginine comprisesL-arginine or D-arginine. In some embodiments, a formulation comprisingarginine comprises L-arginine hydrochloride or D-arginine hydrochloride.In some embodiments, the formulation comprises L-arginine. In someembodiments, the formulation comprises L-arginine hydrochloride. In someembodiments, the formulation comprises arginine at a concentrationranging from 10 mM to 250 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 10 mM to 225 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 10 mM to 200 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 10 mM to 175 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 10 mM to 150 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 10 mM to 125 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 10 mM to 100 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 10 mM to 75 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 10 mM to 50 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 10 mM to 25 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 10 mM to 20 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 20 mM to 250 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 25 mM to 250 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 50 mM to 250 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 75 mM to 250 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 100 mM to 250 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 125 mM to 250 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 150 mM to 250 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 175 mM to 250 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 200 mM to 250 mM. Insome embodiments, the formulation comprises arginine at a concentrationranging from 225 mM to 250 mM. In some embodiments, the formulationcomprises arginine at a concentration ranging from 20 mM to 30 mM, or 15mM to 35 mM. In some embodiments, the formulation comprises arginine ata concentration of 25 mM. In some embodiments, the formulation comprisesarginine at a concentration of 50 mM. In some embodiments, theformulation comprises arginine at a concentration of 75 mM. In someembodiments, the formulation comprises arginine at a concentration of100 mM. In some embodiments, the formulation comprises arginine at aconcentration of 125 mM. In some embodiments, the formulation comprisesarginine at a concentration of 150 mM.

In some embodiments, the formulation comprises glutamic acid at aconcentration ranging from 10 mM to 250 mM. In some embodiments, theformulation comprises glutamic acid at a concentration ranging from 10mM to 200 mM. In some embodiments, the formulation comprises glutamicacid at a concentration ranging from 10 mM to 150 mM. In someembodiments, the formulation comprises glutamic acid at a concentrationranging from 10 mM to 100 mM. In some embodiments, the formulationcomprises glutamic acid at a concentration ranging from 10 mM to 75 mM.In some embodiments, the formulation comprises glutamic acid at aconcentration ranging from 10 mM to 50 mM. In some embodiments, theformulation comprises glutamic acid at a concentration ranging from 10mM to 25 mM. In some embodiments, the formulation comprises glutamicacid at a concentration ranging from 10 mM to 20 mM. In someembodiments, the formulation comprises glutamic acid at a concentrationranging from 20 mM to 250 mM. In some embodiments, the formulationcomprises glutamic acid at a concentration ranging from 25 mM to 250 mM.In some embodiments, the formulation comprises glutamic acid at aconcentration ranging from 50 mM to 250 mM. In some embodiments, theformulation comprises glutamic acid at a concentration ranging from 75mM to 250 mM. In some embodiments, the formulation comprises glutamicacid at a concentration ranging from 100 mM to 250 mM. In someembodiments, the formulation comprises glutamic acid at a concentrationranging from 125 mM to 250 mM. In some embodiments, the formulationcomprises glutamic acid at a concentration ranging from 150 mM to 250mM. In some embodiments, the formulation comprises glutamic acid at aconcentration ranging from 200 mM to 250 mM. In some embodiments, theformulation comprises glutamic acid at a concentration of 50 mM. In someembodiments, the formulation comprises glutamic acid at a concentrationof 75 mM. In some embodiments, the formulation comprises glutamic acidat a concentration of 100 mM. In some embodiments, the formulationcomprises glutamic acid at a concentration of 125 mM. In someembodiments, the formulation comprises glutamic acid at a concentrationof 150 mM.

In some embodiments, the formulation comprises arginine and glutamicacid at a ratio of at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In someembodiments, the formulation comprises arginine and glutamic acid at aratio of greater than or equal to 1:1. In some embodiments, theformulation comprises arginine and glutamic acid at a ratio equal to1:1. In some embodiments, the formulation comprises arginine andglutamic acid at a ratio equal to 2:1. In some embodiments, theformulation comprises arginine and glutamic acid at a ratio equal to3:1. In some embodiments, the formulation comprises arginine andglutamic acid at a ratio equal to 4:1. In some embodiments, theformulation comprises glutamic acid and arginine at a ratio of at least10:1, 5:1, 4:1, 3:1, 2:1, or 1:1.

In some embodiments, the formulation comprises L-histidine. In someembodiments, the formulation comprises histidine at a concentrationranging from 5 mM to 25 mM. In some embodiments, the formulationcomprises histidine at a concentration ranging from 5 mM to 20 mM. Insome embodiments, the formulation comprises histidine at a concentrationranging from 5 mM to 15 mM. In some embodiments, the formulationcomprises histidine at a concentration ranging from 5 mM to 10 mM. Insome embodiments, the formulation comprises histidine at a concentrationranging from 10 mM to 25 mM. In some embodiments, the formulationcomprises histidine at a concentration ranging from 15 mM to 25 mM. Insome embodiments, the formulation comprises histidine at a concentrationranging from 20 mM to 25 mM. In some embodiments, the formulationcomprises histidine at a concentration ranging from 15 mM to 25 mM, orbetween 10 mM to 30 mM. In some embodiments, the formulation compriseshistidine at a concentration of 10 mM. In some embodiments, theformulation comprises histidine at a concentration of 20 mM.

In some embodiments, the formulation comprises glycine at aconcentration ranging from 100 mM to 250 mM. In some embodiments, theformulation comprises glycine at a concentration ranging from 100 mM to200 mM. In some embodiments, the formulation comprises glycine at aconcentration ranging from 100 mM to 150 mM. In some embodiments, theformulation comprises glycine at a concentration ranging from 150 mM to250 mM. In some embodiments, the formulation comprises glycine at aconcentration ranging from 200 mM to 250 mM. In some embodiments, theformulation comprises glycine at a concentration of 150 mM. In someembodiments, the formulation comprises glycine at a concentration of 200mM.

Buffers

In some embodiments of the invention, a formulation comprises a bufferto control pH. Suitable buffers include, for example, acetate, citrate,histidine, phosphate, succinate, tris(hydroxymethyl)aminomethane(“Tris”) and other organic acids. In some embodiments, the formulationcomprises a buffer selected from citrate, histidine, phosphate andsuccinate. In some embodiments, the formulation comprises a buffer at aconcentration ranging from 5 mM to 100 mM. In some embodiments, theformulation comprises a buffer at a concentration ranging from 5 mM to75 mM. In some embodiments, the formulation comprises a buffer at aconcentration ranging from 5 mM to 50 mM. In some embodiments, theformulation comprises a buffer at a concentration ranging from 5 mM to40 mM. In some embodiments, the formulation comprises a buffer at aconcentration ranging from 5 mM to 30 mM. In some embodiments, theformulation comprises a buffer at a concentration ranging from 5 mM to20 mM. In some embodiments, the formulation comprises a buffer at aconcentration ranging from 5 mM to 10 mM. In some embodiments, theformulation comprises a buffer at a concentration ranging from 10 mM to100 mM. In some embodiments, the formulation comprises a buffer at aconcentration ranging from 20 mM to 100 mM. In some embodiments, theformulation comprises a buffer at a concentration ranging from 30 mM to100 mM. In some embodiments, the formulation comprises a buffer at aconcentration ranging from 40 mM to 100 mM. In some embodiments, theformulation comprises a buffer at a concentration ranging from 50 mM to100 mM. In some embodiments, the formulation comprises a buffer at aconcentration ranging from 75 mM to 100 mM. In some embodiments, theformulation comprises a buffer at a concentration of 10 mM. In someembodiments, the formulation comprises a buffer at a concentration of 20mM.

In some embodiments, the formulation comprises phosphate. In someembodiments, the formulation comprises phosphate at a concentrationranging from 5 mM to 50 mM. In some embodiments, the formulationcomprises phosphate at a concentration ranging from 5 mM to 40 mM. Insome embodiments, the formulation comprises phosphate at a concentrationranging from 5 mM to 30 mM. In some embodiments, the formulationcomprises phosphate at a concentration ranging from 5 mM to 20 mM. Insome embodiments, the formulation comprises phosphate at a concentrationranging from 5 mM to 10 mM. In some embodiments, the formulationcomprises phosphate at a concentration ranging from 10 mM to 50 mM. Insome embodiments, the formulation comprises phosphate at a concentrationranging from 20 mM to 50 mM. In some embodiments, the formulationcomprises phosphate at a concentration ranging from 30 mM to 50 mM. Insome embodiments, the formulation comprises phosphate at a concentrationranging from 40 mM to 50 mM. In some embodiments, the formulationcomprises phosphate at a concentration of 10 mM. In some embodiments,the formulation comprises phosphate at a concentration of 20 mM.

In some embodiments, the formulation comprises citrate. In someembodiments, the formulation comprises citrate at a concentrationranging from 5 mM to 50 mM. In some embodiments, the formulationcomprises citrate at a concentration ranging from 5 mM to 40 mM. In someembodiments, the formulation comprises citrate at a concentrationranging from 5 mM to 30 mM. In some embodiments, the formulationcomprises citrate at a concentration ranging from 5 mM to 20 mM. In someembodiments, the formulation comprises citrate at a concentrationranging from 5 mM to 10 mM. In some embodiments, the formulationcomprises citrate at a concentration ranging from 10 mM to 50 mM. Insome embodiments, the formulation comprises citrate at a concentrationranging from 20 mM to 50 mM. In some embodiments, the formulationcomprises citrate at a concentration ranging from 30 mM to 50 mM. Insome embodiments, the formulation comprises citrate at a concentrationranging from 40 mM to 50 mM. In some embodiments, the formulationcomprises citrate at a concentration of 20 mM.

In some embodiments, the formulation comprises succinate. In someembodiments, the formulation comprises succinate at a concentrationranging from 5 mM to 50 mM. In some embodiments, the formulationcomprises succinate at a concentration ranging from 5 mM to 40 mM. Insome embodiments, the formulation comprises succinate at a concentrationranging from 5 mM to 30 mM. In some embodiments, the formulationcomprises succinate at a concentration ranging from 5 mM to 20 mM. Insome embodiments, the formulation comprises succinate at a concentrationranging from 5 mM to 10 mM. In some embodiments, the formulationcomprises succinate at a concentration ranging from 10 mM to 50 mM. Insome embodiments, the formulation comprises succinate at a concentrationranging from 20 mM to 50 mM. In some embodiments, the formulationcomprises succinate at a concentration ranging from 30 mM to 50 mM. Insome embodiments, the formulation comprises succinate at a concentrationranging from 40 mM to 50 mM. In some embodiments, the formulationcomprises succinate at a concentration of 20 mM.

Salts

In some embodiments of the invention, a formulation further comprises asalt. Suitable salts include, for example, sodium chloride, potassiumchloride, sodium sulfate and magnesium chloride. In some embodiments,the formulation comprises a halide. In some embodiments, the halidecomprises an alkali metal halide. In some embodiments, the salt issodium chloride (NaCl). In some embodiments, the formulation comprisesNaCl at a concentration ranging from 50 mM to 175 mM. In someembodiments, the formulation comprises NaCl at a concentration rangingfrom 50 mM to 150 mM. In some embodiments, the formulation comprisesNaCl at a concentration ranging from 50 mM to 125 mM. In someembodiments, the formulation comprises NaCl at a concentration rangingfrom 50 mM to 100 mM. In some embodiments, the formulation comprisesNaCl at a concentration ranging from 50 mM to 75 mM. In someembodiments, the formulation comprises NaCl at a concentration rangingfrom 75 mM to 175 mM. In some embodiments, the formulation comprisesNaCl at a concentration ranging from 100 mM to 175 mM. In someembodiments, the formulation comprises NaCl at a concentration rangingfrom 125 mM to 175 mM. In some embodiments, the formulation comprisesNaCl at a concentration ranging from 150 mM to 175 mM. In someembodiments, the formulation comprises NaCl at a concentration rangingfrom 120 mM to 130 mM, or between 125 mM to 135 mM. In some embodiments,the formulation comprises NaCl at a concentration of 75 mM. In someembodiments, the formulation comprises NaCl at a concentration of 125mM. In some embodiments, the formulation comprises NaCl at aconcentration of 150 mM. In one embodiment, the molar ratio of NaCl toarginine is approximately 5:1. In another embodiment, the molar ratio ofNaCl to histidine is approximately 6:1.

Surfactants

In some embodiments of the invention, a formulation further comprises asurfactant. Exemplary surfactants include nonionic surfactants such aspolysorbates (e.g., polysorbate 20, polysorbate 40, or polysorbate 80);poloxamers (e.g., poloxamer 188); Triton; sodium dodecyl sulfate (SDS);sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-,linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- orstearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine;lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-,myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine(e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, orisostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodiummethyl ofeyl-taurate; and the MONAQUAT™ series (Mona Industries, Inc.,Paterson, N.J.), polyethylene glycol (PEG), polypropylene glycol, andcopolymers of ethylene and propylene glycol (e.g., Pluronics, PF68,etc). Typically, the amount of surfactant added is such that it reducesaggregation of the antibody and minimizes the formation of particulates.For example, a surfactant may be present in a formulation at aconcentration from about 0.001-0.5% (e.g., about 0.075%). In particular,a surfactant may be present in a formulation at a concentration ofapproximately 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, etc. In someembodiments, a surfactant may be present in a formulation at aconcentration of approximately 0.03%. In some embodiments, a surfactantmay be present in a formulation at a concentration of approximately0.07%. In some embodiments, a surfactant may be present in a formulationat a concentration of approximately 0.1%. In some embodiments, aformulation comprises polysorbate 80 (PS80) at a concentration ofapproximately 0.03%. In some embodiments, a formulation comprisespolysorbate 80 (PS80) at a concentration of approximately 0.07%. In someembodiments, a formulation comprises polysorbate 80 (PS80) at aconcentration of approximately 0.05%. In some embodiments, a formulationcomprises polysorbate 80 (PS80) at a concentration of approximately0.1%. Alternatively, or in addition, the surfactant may be added to alyophilized formulation, pre-lyophilized formulation and/or areconstituted formulation.

Other pharmaceutically acceptable carriers, excipients or stabilizerssuch as those described in Remington's Pharmaceutical Sciences 16thedition, Osol, A. Ed. (1980) may be included in the formulation (and/orthe lyophilized formulation and/or the reconstituted formulation)provided that they do not adversely affect the desired characteristicsof the formulation. Acceptable carriers, excipients or stabilizers arenontoxic to recipients at the dosages and concentrations employed andinclude, but are not limited to, additional buffering agents;preservatives; co-solvents; antioxidants including ascorbic acid andmethionine; chelating agents such as EDTA; metal complexes (e.g.,Zn-protein complexes); biodegradable polymers such as polyesters; and/orsalt-forming counterions such as sodium. In some embodiments of theinvention, a formulation comprises an excipient, wherein the excipientis a polyol. Suitable polyol excipients include, for example, mannitoland sorbitol. In some embodiments, the formulation comprises mannitol ata concentration ranging from 50 mM to 200 mM. In some embodiments, theformulation comprises mannitol at a concentration ranging from 60 mM to170 mM. In some embodiments, the formulation comprises sorbitol at aconcentration ranging from 2-8% by weight. In some embodiments, theformulation comprises sorbitol at a concentration ranging from 2.5-5% byweight.

pH and Isoelectric Point (pI)

In some embodiments of the invention, formulations were created withdifferent pH levels in order to determine the effect of pH onformulation properties such as viscosity and stability (e.g., monomerpurity, increase in high molecular weight (HMW) species, loss of maincharge variant and charge distribution). Typically, when creatingformulations, pH values close to the isoelectric point (pI) (the pH atwhich the effective charge on a protein is zero) are avoided becausesolubility is usually minimal at or near the pI value. Virtually allproteins display a V- or U-shaped plot of solubility vs. pH, with thebottom being at the pI value. This behavior is due to minimalelectrostatic repulsion being present at the pI, thereby reducing thecolloidal stability of the protein, which leads to decreased solubility,increased viscosity, and elevated likelihood of aggregation. Generally,as the pH of a formulation either increases or decreases, the overallcharge on the protein increases, leading to increased electrostaticrepulsion and improved colloidal stability. Remarkably, when differentformulations comprising an anti-OSMR antibody were tested, it wasdetermined that pH values not only close to the pI, but actuallyoverlapping it (e.g., pH of 6.0 to 7.5 and pI of 7.0-8.0), wereeffective at maintaining stability, while still allowing antibodyconcentrations of ≥200 mg/mL to be achieved. Additionally, formulationsunder these pH conditions displayed viscosities that were surprisinglylow for high concentration formulations of a monoclonal antibody. Thiswas not expected, as one of skill in the art would have predicted lowersolubility and/or higher viscosity under these conditions.

In some embodiments, pH values in the range of 6.0-7.6 keep theviscosity of the formulation at levels that allow subcutaneousadministration (e.g., less than 30 mPa*s) when the antibodyconcentration is, for example, in the range of approximately 150 mg/mLand approximately 250 mg/mL. In some embodiments, an increase in HMWspecies of an anti-OSMR antibody occurs in formulations at pH<6.0. Insome embodiments, loss of the main charge variant peak of an anti-OSMRantibody in the formulation is correlated with the pH of theformulation. In some embodiments, higher pH formulations have a greaterloss of the main charge variant peak after weeks in storage, with theloss mainly due to formation of acidic species. In certain embodiments,an increase in HMW species or loss of the charge variant peak of theanti-OSMR antibody in storage is determined at 2, 4, 6 or 8 weeks instorage and at approximately 5° C., 25° C. or 40° C. In someembodiments, a formulation according to the present invention has a pHranging from approximately 6.0-7.6. In some embodiments, a formulationaccording to the present invention has a pH ranging from approximately6.6-7.2. In some embodiments, a formulation according to the presentinvention has a pH selected from 6.6, 6.8, 7.0, 7.2 and 7.6.

In some embodiments, a formulation according to the present inventioncomprises an anti-OSMR antibody that has a pI ranging from approximately6.5-8.5. In some embodiments, a formulation according to the presentinvention comprises an anti-OSMR antibody that has a pI ranging fromapproximately 7.2 to 8.0. In some embodiments, a formulation accordingto the present invention comprises an anti-OSMR antibody that has a pIranging from approximately 6.5-8.5 and has a pH that overlaps with pI ofthe anti-OSMR antibody. In some embodiments, a formulation according tothe present invention has an anti-OSMR antibody concentration of atleast 150 mg/mL (e.g., between about 150 mg/mL and about 175 mg/mL,between about 175 mg/mL and 200 mg/mL, between about 200 mg/mL and 225mg/mL, and between about 225 mg/mL and 250 mg/mL), pH ranging from 6.0to 7.6, and a pI ranging from 7 to 8. In one embodiment, the anti-OSMRantibody is present at a concentration of between about 150 mg/mL and210 mg/ml, having a pH ranging from approximately 6.6 to 6.8 and a pIranging from approximately 7.2 to 8.0.

In some embodiments, the formulation is an isoltonic solution. In someembodiments the isotonic formulation comprises an osmolarity rangingbetween 250 and 350 mOsm. In some embodiments, the of the osmolarityformulation ranges between 260-330 mOsm. In some embodiments theosmolarity of the formulation ranges anywhere between 250, 260, 270,280, 290, 300, 310, 320, 330, 340 or 350 mOsm. In some embodiments, theosmolarity of the formulation ranges between 270-300 mOsm.

Viscosity

In some embodiments of the invention, a formulation is a liquid. In someembodiments of the invention, formulations were optimized in order toreduce viscosity, while maintaining high antibody concentration. Using aconstant rate of 0.1 mL/minute, the force required to either aspirate(syringeability) or expel (injectability) the material from/into thesyringe can be recorded. In some embodiments, lower viscosity allows forincreased injectability of a formulation or effective sample transferand preparation during manufacturing. In some embodiments, a formulationhas a viscosity, as measured by microfluidic rheometer, ranging from 1mPa*s to 30 mPa*s. In some embodiments, a formulation has a viscosity ofless than 25 mPa*s, as measured by microfluidic rheometer. In someembodiments, a formulation has a viscosity of less than 20 mPa*s, asmeasured by microfluidic rheometer. In some embodiments, a formulationhas a viscosity of less than 15 mPa*s, as measured by microfluidicrheometer. In some embodiments, a formulation has a viscosity, asmeasured by a microfluidic rheometer, between approximately 1 and 30mPa*s. In some embodiments, a formulation has a viscosity, as measuredby a microfluidic rheometer, between approximately 2 and 30 mPa*s. Insome embodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 4 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 6 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 8 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 10 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 12 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 14 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 16 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 18 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 20 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 22 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 24 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 26 and 30 mPa*s. In someembodiments, a formulation has a viscosity, as measured by amicrofluidic rheometer, between approximately 28 and 30 mPa*s. In someembodiments, a formulation has a shear rate of less than 1000 s⁻¹ at 25°C.

In some embodiments, the formulation has the viscosity such that it isinjectable via a regular syringe and needle combination, the needlehaving a nominal internal diameter of about 0.1 to about 0.6 mm. In someembodiments, the formulation is injectable by a needle having aninternal diameter of about 0.1, or about 0.2 or about 0.3, or about 0.4or about 0.5, or about 0.6 mm. In some embodiments, the formulation hasthe viscosity such that it is injectable via a regular syringe andneedle combination, the needle having a nominal internal diameter ofabout 0.18 to about 0.3 mm. In some embodiments, the formulation has aviscosity such that it is injectable using a needle having an internaldiameter between about 0.184 mm to about 0.260 mm diameter. In someembodiments, the formulation has the viscosity such that it isinjectable via a regular syringe and needle combination, the needlehaving a nominal internal diameter of about 0.184 to 0.210 mm. In someembodiments, the formulation has a viscosity such that it is injectableusing 27G ½″ gauge needle and a 2 ml syringe. In some embodiments, thepound force required to inject the formulation at a constant rate of 0.1mL/second is less than about 8.0 pound force. In some embodiments, thepound force required to inject the formulation at a constant rate of 0.1mL/second is less than about 8 pound force, less than about 7.5 poundforce, or less than about 6.9 pound force, less than about 6.8 poundforce, less than about 6.7 pound force, less than about 6.7 pound force,less than about 6.6 pound force or less than about 6.5 pound force.

Stability

In some embodiments of the invention, formulations were optimized inorder to increase stability. The stability of an antibody formulationcan be quantified in several ways. In some embodiments, stability of anantibody formulation is characterized by the amount of HMW species of ananti-OSMR antibody or the rate of increase of the amount of HMW speciesof an anti-OSMR antibody. In certain embodiments, the rate of increaseof HMW species is determined at 2, 4, 6 or 8 weeks in storage and atapproximately 5° C., 25° C. or 40° C. In some embodiments, stability ofan antibody formulation is characterized by charge distribution, e.g., achange in the amount of the charge variant peaks of the antibody. Insome embodiments, stability of an antibody formulation is characterizedby dynamic light scattering, analytical ultracentrifugation (AUC), fieldflow fractionation (FFF), isoelectric focusing and ion exchangechromatography (IEX). In some embodiments, stability of an antibodyformulation is characterized by partial dissociation as measured bysodium-dodecyl sulfate capillary electrophoresis (CE-SDS) and/orsodium-dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).

The stability of an anti-OSMR antibody, and the capability of theformulation to maintain stability of the anti-OSMR antibody, may beassessed over extended periods of time (e.g., weeks or months). In thecontext of a formulation, a stable formulation is one in which theantibody therein essentially retains its physical and/or chemicalintegrity and biological activity upon storage and during processes suchas freeze/thaw, mechanical mixing and lyophilization. Antibody stabilitycan be measured by formation of high molecular weight (HMW) aggregates,shift of charge profiles, and change in particle size.

Stability of an antibody may be assessed relative to the biologicalactivity or physiochemical integrity of the antibody over extendedperiods of time. For example, stability at a given time point may becompared against stability at an earlier time point (e.g., uponformulation day 0), against unformulated antibody, or against adifferently formulated antibody and the results of this comparisonexpressed as a percentage. Preferably, the antibody formulations of thepresent invention maintain at least 100%, at least 99%, at least 98%, atleast 97% at least 95%, at least 90%, at least 85%, at least 80%, atleast 75%, at least 70%, at least 65%, at least 60%, at least 55% or atleast 50% of the antibody's biological activity, physiochemicalintegrity, and/or particle size over an extended period of time (e.g.,as measured over at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,18, 24, or 36 months, at room temperature or under accelerated storageconditions). In some embodiments, the percent values indicating proteinlevels as disclosed herein or throughout the specification, areexpressed relative to the total protein in the formulation. In someembodiments, the relative values of any particular species of theproduct, as disclosed herein or throughout the specification, such asthe monomeric IgG form or species, or the high molecular weight (HMW)form, or the aggregated forms, are expressed in relation to therespective values of the total product. In some embodiments, the percentvalues of any particular species of the antibody are expressed relativeto the total amount of all antibody-related species in the formulation.In some embodiments, less than 5%, 4%, 3%, 2%, 1%, or 0.5% of ananti-OSMR antibody exists as HMW species in a formulation. In someembodiments, the amount of HMW species in a formulation increases lessthan 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25° C. for more than 2weeks. In some embodiments, upon storage at 25° C. for 4 weeks, theamount of HMW species in the formulation increases approximately between0.3% to 0.7%, approximately between 0.3% to 0.6%, or approximatelybetween 0.3% to 0.5%. In some embodiments, at least 90%, 92%, 94%, 95%,96%, 97%, 98%, or 99% of an anti-OSMR antibody exists as monomer in astable formulation. In some embodiments, the amount of monomer decreasesless than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25°C. for more than 2 weeks, for example, for 4 weeks.

Delivery

In some embodiments of the invention, formulations comprise highanti-OSMR antibody concentrations suitable for subcutaneous,intradermal, intramuscular and/or intra-articular delivery. In someembodiments, a formulation comprises an anti-OSMR antibody at aconcentration of at least approximately 50 mg/mL. In some embodiments, aformulation comprises an anti-OSMR antibody at a concentration of atleast approximately 75 mg/mL. In some embodiments, a formulationcomprises an anti-OSMR antibody at a concentration of at leastapproximately 100 mg/mL. In some embodiments, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 125mg/mL. In some embodiments, a formulation comprises an anti-OSMRantibody at a concentration of at least approximately 150 mg/mL. In someembodiments, a formulation comprises an anti-OSMR antibody at aconcentration of at least approximately 175 mg/mL. In some embodiments,a formulation comprises an anti-OSMR antibody at a concentration of atleast approximately 200 mg/mL. In some embodiments, a formulationcomprises an anti-OSMR antibody at a concentration of at leastapproximately 225 mg/mL. In some embodiments, a formulation comprises ananti-OSMR antibody at a concentration of at least approximately 250mg/mL.

In some embodiments, the volume of an anti-OSMR antibody formulationdelivered by subcutaneous, intradermal, intramuscular and/orintra-articular injection is 10 mL or less. In some embodiments, thevolume of an anti-OSMR antibody formulation delivered by subcutaneous,intradermal, intramuscular and/or intra-articular injection is 5 mL orless. In some embodiments, the volume of an anti-OSMR antibodyformulation delivered by subcutaneous, intradermal, intramuscular and/orintra-articular injection is 4 mL or less. In some embodiments, thevolume of an anti-OSMR antibody formulation delivered by subcutaneous,intradermal, intramuscular and/or intra-articular injection is 3 mL orless. In some embodiments, the volume of an anti-OSMR antibodyformulation delivered by subcutaneous, intradermal, intramuscular and/orintra-articular injection is 2 mL or less. In some embodiments, thevolume of an anti-OSMR antibody formulation delivered by subcutaneous,intradermal, intramuscular and/or intra-articular injection is 1 mL orless. In some embodiments, the volume of an anti-OSMR antibodyformulation delivered by subcutaneous, intradermal, intramuscular and/orintra-articular injection is 0.5 mL or less.

In some embodiments, the volume of an anti-OSMR antibody formulationdelivered by subcutaneous injection is 10 mL or less. In someembodiments, the volume of an anti-OSMR antibody formulation deliveredby subcutaneous injection is 5 mL or less. In some embodiments, thevolume of an anti-OSMR antibody formulation delivered by subcutaneousinjection is 4 mL or less. In some embodiments, the volume of ananti-OSMR antibody formulation delivered by subcutaneous injection is 3mL or less. In some embodiments, the volume of an anti-OSMR antibodyformulation delivered by subcutaneous injection is 2 mL or less. In someembodiments, the volume of an anti-OSMR antibody formulation deliveredby subcutaneous injection is 1 mL or less. In some embodiments, thevolume of an anti-OSMR antibody formulation delivered by subcutaneousinjection is 0.5 mL or less. In some embodiments the volume of ananti-OSMR antibody formulation delivered by subcutaneous injection is 3mL. In some embodiments the volume the volume of an anti-OSMR antibodyformulation delivered by subcutaneous injection is 2 mL. In someembodiments the volume the volume of an anti-OSMR antibody formulationdelivered by subcutaneous injection is 1 mL. In some embodiments thevolume of an anti-OSMR antibody formulation delivered by subcutaneousinjection is 0.5 mL.

In some embodiments, subcutaneous injection of the anti-OSMR antibodyformulation can be performed in the upper arm, the anterior surface ofthe thigh, the lower portion of the abdomen, the upper back or the upperarea of the buttock. In some embodiments, the site of injection isrotated.

In some embodiments, formulations of the present invention may bedesigned for delivery by any suitable route, including but not limitedto, subcutaneous, intradermal, intra-articular, oral, rectal, andvaginal, and by parenteral routes, including intravenous andintra-arterial injection, and intramuscular injection.

Kits

The present invention further provides kits or other articles ofmanufacture which contain the formulation of the present invention andprovides instructions for its reconstitution (if lyophilized) and/oruse. Kits or other articles of manufacture may include a container, aneedle, and any other articles, devices or equipment useful insubcutaneous administration. Suitable containers include, for example,bottles, vials, syringes (e.g., pre-filled syringes), subcutaneouspumps, ampules, cartridges, reservoirs, or lyo-jects. The container maybe formed from a variety of materials such as glass or plastic. In someembodiments, a container is a prefilled syringe. Suitable pre-filledsyringes include, but are not limited to, borosilicate glass syringeswith baked silicone coating, borosilicate glass syringes with sprayedsilicone, or plastic resin syringes without silicone.

Typically, the container may holds formulations and a label on, orassociated with, the container that may indicate directions forreconstitution and/or use. For example, the label may indicate that theformulation is reconstituted to antibody concentrations as describedabove. The label may further indicate that the formulation is useful orintended for, for example, subcutaneous administration. In someembodiments, a container may contain a single dose of a stableformulation containing a therapeutic antibody (e.g., an anti-OSMRantibody). In various embodiments, a single dose of the stableformulation is present in a volume of less than about 10 mL, 5.0 mL, 4.0mL, 3.5 mL, 3.0 mL, 2.5 mL, 2.0 mL, 1.5 mL, 1.0 mL, or 0.5 mL.

Alternatively, a container holding the formulation may be a multi-usevial, which allows for repeat administrations (e.g., from 2-6administrations) of the formulation. Kits or other articles ofmanufacture may further include a second container comprising a suitablediluent (e.g., BWFI, saline, buffered saline). Upon mixing of thediluent and the formulation, the final antibody concentration in thereconstituted formulation will generally be at least 150 mg/mL (e.g., atleast 160 mg/mL, at least 170 mg/mL, at least 180 mg/mL, at least 190mg/mL, at least 200 mg/mL). Kits or other articles of manufacture mayfurther include other materials desirable from a commercial and userstandpoint, including other buffers, diluents, preservatives, filters,needles, syringes, and package inserts with instructions for use.

Treatment of Diseases and Disorders Associated With OSMR

Anti-OSMR antibody formulations and compositions of the presentinvention are used to treat an autoimmune disorder, inflammatorydisorder, or a disorder associated with extracellular matrix depositionor remodeling. In treating these disorders, the anti-OSMR antibody maytarget OSMR-expressing cells of the immune system for destruction and/ormay block the interaction of OSMR with OSM and/or IL-31. Diseases ordisorders that are associated with OSMR-mediated signaling areparticularly amenable to treatment with the anti-OSMR antibodies of thepresent invention. One such disorder is pruritus. Other diseases anddisorders that are associated with OSMR-mediated signaling and areparticularly amenable to treatment with the anti-OSMR antibodies of thepresent invention include, but are not limited to, inflammation, pain,prurigo nodularis, dermatitis, atopic dermatitis, asthma, autoimmunedisease, paraneoplastic autoimmune diseases, cartilage inflammation,fibrosis (including, but not limited to, pulmonary fibrosis and skinfibrosis), fibrotic disease, chronic obstructive pulmonary disease(COPD), interstitial pneumonitis, abnormal collagen deposition, systemiccutaneous amyloidosis, primary cutaneous amyloidosis, Behcet's disease,nasal polyposis, liver cirrhosis, cartilage degradation, bonedegradation, arthritis, rheumatoid arthritis, juvenile arthritis,juvenile rheumatoid arthritis, pauciarticular juvenile rheumatoidarthritis, polyarticular juvenile rheumatoid arthritis, systemic onsetjuvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenileenteropathic arthritis, juvenile reactive arthritis, juvenile Reter'sSyndrome, SEA Syndrome (Seronegativity, Enthesopathy, ArthropathySyndrome), juvenile dermatomyositis, juvenile psoriatic arthritis,juvenile scleroderma, juvenile systemic lupus erythematosus, juvenilevasculitis, pauciarticular rheumatoid arthritis, polyarticularrheumatoid arthritis, systemic onset rheumatoid arthritis, ankylosingspondylitis, enteropathic arthritis, reactive arthritis, Reter'sSyndrome, SEA Syndrome (Seronegativity, Enthesopathy, ArthropathySyndrome), dermatomyositis, psoriatic arthritis, scleroderma,scleroderma-associated interstitial lung disease, vasculitis, myolitis,polymyolitis, dermatomyolitis, polyarteritis nodossa, Wegener'sgranulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis,scleroderma, sclerosis, primary biliary sclerosis, sclerosingcholangitis, Sjogren's syndrome, psoriasis, plaque psoriasis, guttatepsoriasis, inverse psoriasis, pustular psoriasis, erythrodermicpsoriasis, dermatitis, atherosclerosis, lupus, Still's disease, SystemicLupus Erythematosus (SLE), myasthenia gravis, inflammatory bowel disease(IBD), Crohn's disease, ulcerative colitis, celiac disease, multiplesclerosis (MS), asthma, COPD, rhinosinusitis, rhinosinusitis withpolyps, eosinophilic esophagitis, eosinophilic bronchitis, bronchitis,Guillain-Barre disease, Type I diabetes mellitus, thyroiditis (e.g.,Graves' disease), Addison's disease, Reynaud's phenomenon, autoimmunehepatitis, GVHD, transplantation rejection, kidney damage,cardiovascular disease, infection, sepsis, HIV infection, trauma, kidneyallograft nephropathy, IgA nephropathy, diabetic nephropathy, diabeticretinopathy, macular degeneration, biliary atresia, congestive heartfailure, atherosclerosis, restenosis, radiation-induced fibrosis,chemotherapy-induced fibrosis, burns, surgical trauma,glomerulosclerosis, and the like.

Formulations, compositions and methods of the present invention may beused to effectively treat individuals suffering from or susceptible topruritus. The terms, “treat” or “treatment,” as used herein, refers toamelioration of one or more symptoms associated with pruritus,prevention or delay of the onset of one or more symptoms of pruritus,and/or lessening of the severity or frequency of one or more symptoms ofpruritus.

EXAMPLES

While certain formulations, compositions and methods of the presentinvention have been described with specificity in accordance withcertain embodiments, the following examples serve only to illustrate thecompounds of the invention and are not intended to limit the same.

Example 1: Characterization of Anti-OSMR Antibody

The exemplary anti-OSMR antibodies described herein are fully humanmonoclonal antibodies that specifically inhibit IL-31 and oncostatin M(OSM)-induced activation of the IL-31 receptor and type II OSM receptor,respectively, through binding to OSMRβ, the subunit common to bothreceptors. The antibody comprises two light chains and two heavy chains.The light chain contains a lambda constant region. The constant regionsof the heavy chain contain the CH1, hinge, and CH2 domains of a humanimmunoglobulin IgG4 antibody fused to the CH3 domain of a human IgGantibody. Additionally, the heavy chain of the anti-OSMR antibodycontains a S228P modification to improve stability and a N297Qmodification to remove an N-linked glycosylation site.

An exemplary anti-OSMR antibody comprises a heavy chain amino acidsequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ IDNO: 2. The exemplary anti-OSMR antibody also comprises a heavy chainvariable domain amino acid sequence of SEQ ID NO: 3 and a light chainvariable domain amino acid sequence of SEQ ID NO: 4. The exemplaryanti-OSMR antibody also comprises a heavy chain variable domain CDR1(HCDR1) of SEQ ID NO: 5, a heavy chain variable domain CDR2 (HCDR2) ofSEQ ID NO: 6, a heavy chain variable domain CDR3 (HCDR3) of SEQ ID NO:7, a light chain variable domain CDR1 (LCDR1) of SEQ ID NO: 8, a lightchain variable domain CDR2 (LCDR2) of SEQ ID NO: 9, and a light chainvariable domain CDR3 (LCDR3) of SEQ ID NO: 10. The exemplary anti-OSMRantibody also comprises a heavy chain signal peptide amino acid sequenceof SEQ ID NO: 11, a heavy chain amino acid sequence comprising IgG4 CH1,hinge, and CH2 domains of SEQ ID NO: 12, a heavy chain IgG CH3 domainamino acid sequence of SEQ ID NO: 13 and a light chain IgG lambdaconstant domain amino acid sequence of SEQ ID NO: 14.

Charge heterogeneity was assessed by imaged capillary isoelectricfocusing (icIEF). The protein isoforms were separated based on pI andthe elution profile was monitored by UV absorbance at 280 nm.

Example 2: Formulation Design and Preparation

Four rounds of formulations were created in order to test the effect ofprotein concentration, buffer species, pH and inclusion of excipients onvariables such as viscosity and stability. Table 1, Table 2, Table 3 andTable 4 below detail the formulation designs for the four rounds offormulations.

TABLE 1 Round 1 Formulation Design Target protein Target Citrate HisPhosphate Succinate Arg NaCl Sorb. PS 80 Sample (mg/ml) pH (mM) (mM)(mM) (mM) (mM) (mM) (wt %) (%) F01 100 6.6 20 0 0 0 150 0 0 0.075 F02125 6.6 20 0 0 0 150 0 0 0.075 F03 150 6.6 20 0 0 0 150 0 0 0.075 F04150 6 0 0 0 20 0 75 2.5 0.075 F05 50 6.6 0 20 0 0 0 150 0 0.075 F06 1007.6 0 20 0 0 0 0 5 0.075 F07 100 7.2 0 0 20 0 0 0 5 0.075 F08 150 7.2 020 0 0 0 0 5 0.075 F09 175 7.6 0 20 0 0 75 75 0 0.075 F10 125 7.2 0 20 00 25 0 5 0.075 Fl 1 50 6.6 0 0 20 0 0 150 0 0.075 F12 100 6 0 0 20 0 0 05 0.075 F13 50 7.6 0 0 20 0 0 150 0 0.075 F14 150 6.6 0 0 0 20 25 0 50.075 F15 125 5.4 20 0 0 0 0 0 5 0.075 F16 100 5.4 0 0 0 20 0 75 2.50.075

TABLE 2 Round 2 Formulation Design Target protein citrate His Phosphatesuccinate Arg Glu Gly NaCl mannitol PS 80 Sample (mg/ml) pH (mM) (mM)(mM) (mM) (mM) (mM) (mM) (mM) (mM) (%) F01 200 6.57 20  0  0  0 150  0 0  0  0 0.1 F02 200 6.75  0  0  0  0 150  0  0  0  0 0.1 F03 200 6.58 0  0 10  0  50  0  0  75  0 0.1 F04 200 6.74  0  0  0  0  25  0 200  0 0 0.1 F05 200 6.66  0 20  0  0  0 150  0  0  0 0.1 F06 200 6.56  0  0 0 20 150  0  0  0  0 0.1 F07 200 6.98  0 20  0  0  50  0 150  0  0 0.1F08 200 7.12  0  0 20  0  50  0  0  0 170 0.1 F09 200 6.84  0  0  0 20 25  0  0 125  0 0.1 F10 200 6.59  0  0  0  0  25  0  0 125  0 0.1 F11200 6.68  0 10  0  0  50  50  0  0  60 0.1 F12 200 6.95  0 10  0  0  50 50  0  0  60 0.1 F13 200 7.08  0 10  0  0  50  50  0  0  60 0.1 F14 2006.97  0  0 10  0 100 100  0  0  0 0.1 F15 200 6.66  0 10  0  0 100 100 0  0  0 0.1 F16 200 6.60  0 10  0  0  0  0  0  75 120 0.1 F17 200 6.57 0 10  0  0  0  0  0 150  0 0.1 F18 200 6.58  0 10  0  0 150  0  0  0  00.1

TABLE 3 Round 3 Formulation Design Target citrate His Phosphatesuccinate Arg Glu Gly NaCl mannitol PS 80 Sample pH (mM) (mM) (mM) (mM)(mM) (mM) (mM) (mM) (mM) (%) F01 6.6 0 20 0 0  25 0 0 125 0 0.075 F026.6 0 20 0 0 150 0 0  0 0 0.075 F03 6.6 0 20 0 0  75 0 0  75 0 0.075

TABLE 4 Round 4 Formulation Design Target Protein Target citrate HisPhosphate succinate Arg Glu Gly NaCl mannitol PS 80 Sample (mg/ml) pH(mM) (mM) (mM) (mM) (mM) (mM) (mM) (mM) 1 (mM) (%) F01 200 6.6 0 20 0 0 25 0 0 125 0 variable F02 200 6.6 0 20 0 0 150 0 0  0 0 variable

Formulations for Rounds 1, 2 and 3 were prepared by dialyzing the bulkdrug substance (BDS) against the formulation placebo (buffer andtonicity modifiers) with Slide-A-Lyzer Mini Dialysis devices (20 kDMWCO, 2 mL capacity). The following dialysis procedure was utilized: 4hours against milliQ water, 2 hours at room temperature against placebowith orbital shaking at 300 rpm (3 mm-orbital radius shaker) followed byan additional 2 exchanges against placebo and another 4 hours at roomtemperature (2 hours per exchange, 300 rpm orbital shaking), and finallyanother buffer exchange and dialysis at 2-8° C. (orbital shaking, 300rpm) for an additional 17-24 hours. If needed, polysorbate 80 (PS80) wasspiked into a given formulation from a 10% (w/v) stock solution preparedin milliQ water. Formulations for Round 4 were prepared in a similarmanner, with the exception that dialysis was conducted with aSlide-A-Lyzer Dialysis Cassette to reduce the shear experienced by thePS80-free protein during dialysis. All samples were concentrated to thetarget concentration using centrifugal spin concentrators.

The drug substance comrpising an API concentration of 209 mg/mL in aformulation buffer comprising 20 mM L-histidine, 25 mM L-argininehydrochloride, 125 mM sodium chloride, 0.05% (w/v) polysorbate 80, pH6.6-6.8 was subjected to stress, stability, freeze thaw and drugproduction stress studies. For in-use compatibility studies, the drugsubstance was diluted to 180 mg/mL by formulation buffer. A placebocontrol is 20 mM L-Histidine, 25 mM L-Arginine-HCl, 125 mM NaCl, 0.05%(w/v) PS80, pH 6.6.

Sub-ambient differential scanning calorimetry (DSC) analysis determinedthe glass transition temperature (Tg′) of the formulation at both 208.8mg/mL and 180 mg/mL, to be ˜−34.3° C. Density measurements taken bydensitometer at 25° C. on the formulation at 180 mg/mL, as well asplacebo, were 1.0588 g/cm³ and 1.0050 g/cm³, respectively. All sampleswere free of visible particulates. Over the course of 24 hours, nochange in appearance was detected in comparison to time zero.

For the preparation of individual stability samples, each formulation(bulk material) was sterile filtered using a Millipore Millex-GV syringefilter (0.22 μm). After filtration, 0.5 mL was aliquotted into 1 mLglass vials, stoppered (13 mm rubber stopper), and sealed with crimpedaluminum caps. Sterile filtering and aliquotting was conducted in abiosafety cabinet using materials (i.e., vials, stoppers, etc.) that hadbeen previously sterilized.

Injectability was assessed by Instron Mechanical Tester, examined thepound-force required to expel the drug product at a constant rate of0.1-mL/min, using different needle gauges and lengths, as well as sampletemperatures of 18° C. and 25°. Results show that the drug product at180 mg/mL, at 25° C., expelled via a 27G ½″ needle required 6.5pound-force.

Example 3: Viscosity

The viscosity of samples from Round 1 and Round 2 was measured fornon-stressed material (nominally t0). Viscosity was measured using aRheosense m-VROC rheometer at a shear rate of 1000 s⁻¹ and a temperatureof 25° C. A 100 μL Hamilton gas-tight syringe filled with 100 μL(nominally) of a given formulation was used to perform a measurement.Generally, 4 measurements per formulation were collected with the last 2being averaged and reported as the formulation viscosity. The viscosityresults from Round 1 are shown below in Table 5, the viscosity resultsfrom Round 2 are shown below in Table 6, and the viscosity results fromRound 3 are shown below in Table 7. A graph illustrating the effect ofprotein concentration on viscosity from two Round 3 formulations isshown in FIG. 1.

Concentration of the anti-OSMR antibody was determined usingUV-absorbance spectroscopy. Briefly, absorbance of diluted the anti-OSMRantibody was determined at 280 nm in a 1 cm path-length UV transparentcuvette and corrected for scattering by subtracting out the absorbanceof the sample at 320 nm. Absorbance was determined against a blankwithout protein and converted to protein content utilizing Beer's law(ε_(280, 1 cm)=1.62 ml/mg*cm). Since samples were diluted to make themeasurement, it was necessary to multiply this concentration by thedilution factor (gravimetric) to obtain actual concentration.

TABLE 5 Round 1 Viscosity Actual Conc. Sample Actual pH (mg/mL) Visc.(mPa*s) F01 6.60 96.0 2.3 F02 6.59 126.0 3.2 F03 6.57 144.6 5.3 F04 6.01145.0 6.3 F05 6.57 49.4 1.3 F06 6.89 98.8 3.3 F07 7.17 100.7 3.1 F086.60 147.4 8.2 F09 7.50 166.7 8.3 F10 7.19 126.5 4.5 F11 6.54 51.2 1.4F12 6.09 95.9 3.1 F13 7.47 49.6 1.4 F14 6.56 149.9 7.0 F15 5.48 119.65.1 F16 5.39 100.6 2.8

TABLE 6 Round 2 Viscosity Actual Conc. Sample Actual pH (mg/mL) Visc.(mPa*s) F01 6.57 206.0 15.4 F02 6.75 205.7 15.9 F03 6.58 200.7 16.2 F046.74 197.6 22.3 F05 6.66 201.2 22.3 F06 6.56 204.0 15.4 F07 6.98 201.020.0 F08 7.12 201.4 20.9 F09 6.84 201.3 16.7 F10 6.59 195.2 14.6 F116.68 190.5 16.3 F12 6.95 195.0 19.9 F13 7.08 191.0 18.5 F14 6.97 193.817.2 F15 6.66 195.5 16.9 F16 6.60 196.0 18.9 F17 6.57 199.8 17.1 F186.58 198.5 15.1

TABLE 7 Round 3 Viscosity Actual Conc. Temperature Shear Rate Sample(mg/mL) (° C.) (1/s) Visc. (mPa*s) F01 175.97 25 1000 10.81 F01 206.9125 1000 19.40 F01 229.02 25 700 38.11 F01 253.07 25 500 75.27 F02 179.025 1000 9.63 F02 201.7 25 1000 16.65 F02 230.6 25 700 32.29 F02 252.2 25500 59.47

The viscosities were relatively low for all formulations in Round 1,even for those above 150 mg/mL protein (e.g., the viscosity of F09 wasonly 8.3 mPa*s at 166 mg/ml). Regarding the viscosity modulating effectsof the excipients, Arg*HCl appeared to have the largest impact onviscosity reduction at equal concentration of protein. NaCl alsoappeared to reduce viscosity, although not as effectively as Arg*HCl.Formulations containing sorbitol as the tonicity modifier generallyexhibited higher viscosities. The effects of pH and buffer on viscositywere not readily apparent. In general, the viscosity increased in aprotein concentration dependent manner, apparently largely independentof pH.

In Round 2, it was found that lower pH values (in the range of 6.6-7.2)reduced the viscosity when the protein concentration was approximately200 mg/mL. It was also found that Arg and NaCl were particularlyeffective at lowering viscosity. All Round 2 formulations exhibitedviscosity values <23 cP, which is considered excellent for a monoclonalantibody at 200 mg/mL. FIG. 1 illustrates that the viscosities of thesetwo formulations can be higher than 30 cp at certain concentrations.

Viscosity of the drug substance in 20 mM L-histidine, 25 mM L-argininehydrochloride, 125 mM sodium chloride, 0.05% (w/v) polysorbate 80, pH6.6 was measured at various controlled temperatures (4° C., 15° C., 18°C., 25° C., and 35° C.). Three (3) data sets were measured for eachtemperature. Tabular results for samples analyzed at 208 mg/mL and at180 mg/mL are outlined in Tables 8 and 9, respectively. FIG. 2illustrates the change in viscosities of the two formulation samplesover the range of temperatures indicated. As is shown in FIG. 2,viscosity results tested by rheometry at various controlled temperatures(4° C., 15° C., 18° C., 25° C., and 35° C.), at both 180 mg/mL and 209mg/mL exhibited a significant decrease in viscosity with increasingtemperature and/or lower active pharmaceutical ingredient (API)concentration.

TABLE 8 Viscosity of 208.8 mg/mL target protein concentration at varyingtemperatures Viscosity by Rheometry at 208.8 mg/mL Shear ShearTemperature Speed Stress Rate Torque Viscosity (° C.) Test # (RPM)(dyne/cm²) (1/s) (%) (cP)  5° C. 1  2.5 14.81  18.8 62.9 79.1 2  3.018.07  22.5 78.5 80.0 3  3.5 21.27  26.3 92.5 81.0 15° C. 1  6.5 19.01 48.8 82.4 39.4 2  7.0 20.88  52.5 90.7 39.8 3  7.5 22.28  56.3 96.839.7 18° C. 1  7.5 18.55  56.3 80.6 33.0 2  8.2 20.23  61.5 87.8 32.9 3 8.6 21.50  64.5 93.5 33.3 25° C. 1 12.0 21.15  90.0 91.9 23.5 2 12.221.70  91.5 94.3 23.8 3 12.4 22.23  93.0 96.7 23.9 35° C. 1 15.0 21.01112.5 91.3 18.9 2 15.5 21.84 116.3 94.8 18.9 3 16.0 23.02 120.0 99.219.1

TABLE 9 Viscosity of 180 mg/mL target protein concentration at varyingtemperatures Viscosity by Rheometry at 180 mg/mL Shear Shear TemperatureSpeed Stress Rate Torque Viscosity (° C.) Test # (RPM) (dyne/cm2) (1/s)(%) (cP)  5° C. 1  7.3 20.51 54.8 88.9 37.5 2  7.5 21.15 56.3 91.8 37.63  7.7 21.82 57.8 94.9 37.8 15° C. 1 13.0 20.03 97.5 87.1 20.6 2 13.520.97 101.3 91.2 20.7 3 14.0 21.82 105 94.9 20.8 18° C. 1 15.0 19.93112.5 86.7 17.6 2 15.5 20.58 116.3 89.7 17.7 3 16.0 21.22 120 92.3 17.725° C. 1 20.0 19.50 150 84.3 13.0 2 20.7 19.91 155.3 86.9 12.8 3 21.420.67 160.5 90.0 12.9 35° C. 1 30.0 20.72 225 90.1  9.2 2 31.0 21.45232.5 93.2  9.2 3 32.0 22.46 240 97.5  9.4

Example 4: Stability of the Different Formulations Over a Course of 4Weeks

Samples from Round 1 were tested to determine the effect of proteinconcentration, buffer species, pH, and inclusion of other excipients(Arg, NaCl, Sorbitol) on storage stability of the anti-OSMR antibody.Samples were analyzed after they were stored for two weeks at 40° C.(t2) or after they were stored for four weeks at 25° C. (t4). Initialosmolality of the samples from Round 1 are shown below in Table 10 andinitial osmolality of the samples from Round 2 are shown below in Table11. Actual pH values and protein concentrations of the samples fromRound 1 and Round 2 are included above in Table 5 and Table 6,respectively. Protein precipitation was visible in the Round 1 F15 andF16 samples stored for 2 weeks at 40° C.

TABLE 10 Round 1 Osmolality Sample Osmolality (mOsm/kg) F01 336 F02 340F03 341 F04 363 F05 319 F06 345 F07 357 F08 359 F09 315 F10 388 F11 334F12 351 F13 341 F14 423 F15 372 F16 349

TABLE 11 Round 2 Osmolality Sample Osmolality (mOsm/kg) F01 341 F02 288F03 283 F04 N/A F05 N/A F06 347 F07 N/A F08 N/A F09 369 F10 317 F11 203F12 N/A F13 N/A F14 237 F15 229 F16 322 F17 323 F18 311

Monomer Purity

Size-exclusion chromatography was also performed on Round 1 and Round 2samples to determine monomer purity at t0, after two weeks (t2) andafter four weeks (t4), while Round 4 samples were tested for monomerpurity at after freeze-thaw and agitation. Size exclusion chromatography(SEC) separates molecules based on their size by filtration through agel. The gel consists of spherical beads containing pores of a specificsize distribution. Separation occurs when molecules of different sizesare included or excluded from the pores within the matrix. Smallmolecules diffuse into the pores and their flow through the column isretarded according to their size, while large molecules do not enter thepores and are eluted in the column's void volume. Consequently,molecules separate based on their size as they pass through the columnand are eluted in order of decreasing molecular weight (MW). Operatingconditions and gel selection depend on the application and the desiredresolution. Two common types of separations performed by SEC arefractionation and desalting (or buffer exchange.)

Exemplary monomer purity data comparing t0 and t2 at 40° C., t0 and t4at 25° C. and t0 and t4 at 5° C. from Round 1 are provided in Table 12.Exemplary monomer purity data comparing t0 and t4 at 40° C., t0 and t4at 25° C. and t0 and t4 at 5° C. from Round 2 are provided in Table 13.Exemplary monomer purity data comparing agitated and freeze/thaw (F/T)samples to controls are provided in Table 14. The percentage of lowmolecular weight (LMW) species and high molecular weight (HMW) speciesin Round 1 and Round 2 samples was also determined by SEC. Exemplary LMWdata comparing t0 and t2 from Round 1 are provided in Table 15.Exemplary LMW data comparing t0 and t4 from Round 2 at 25° C. areprovided in Table 16. Exemplary LMW data comparing t0 and t4 from Round2 at 5° C. are provided in Table 17. Exemplary HMW data comparing t0 andt2 from Round 1 are provided in Table 18. Exemplary HMW data comparingt0 and t4 at 25° C. from Round 1 are provided in Table 19. Exemplary HMWdata comparing t0 and t4 at 5° C. from Round 1 are provided in Table 20.Exemplary HMW data comparing t0 and t2 at 40° C. from Round 2 areprovided in Table 21. Exemplary HMW data comparing t0 and t4 from Round2 at 25° C. are provided in Table 22. Exemplary HMW data comparing t0and t4 from Round 2 at 5° C. are provided in Table 23. Exemplary HMWdata comparing agitated and F/T samples to controls are provided inTable 24 and Table 25. An exemplary chromatogram showing HMW species instressed samples (F02 at 40° C.) is presented in FIG. 3.

The SEC data from t2 of Round 1 indicate that the anti-OSMR antibody wasprone to high molecular weight formation under stressed conditions andthat the formation of low molecular weight species was minimal for mostsamples. The SEC data from t2 of Round 1 indicate that the highestmonomer loss was observed in sample F04, when succinate was used at pH6.0. In Round 1, the smallest monomer loss was observed in samples F05,F06 and F10, which contained histidine buffer with proteinconcentrations of 50, 100 and 125 mg/mL, respectively. At the proteinconcentration of 150 mg/mL, there was less monomer loss in samplescontaining sorbitol (F08 and F14), than in the sample with arginine(F03).

The SEC data from t4 at 25° C. for Round 1 indicate trends similar tothose from the t2 data in that a higher loss of monomer was seen informulations at pH<6.0. Additionally, higher loss of monomer was seen inphosphate formulations at pH 7.2 and 7.6 (F07 and F13, respectively).Histidine and citrate formulations compared similarly in terms ofmonomer loss. Monomer loss was due almost solely HMW formation(primarily HMW 2). Negligible monomer loss was observed for almost allformulations stored at 2-8° C.

The SEC data from the agitation and F/T samples (Round 4) indicate thatpurity was effectively unchanged (vs. t0) for all samples except for theagitation samples that did not contain PS80. For these samples, therewas an increase in both HMW 1 (aggregate) and HMW 2 (presumably dimer).These changes were much greater for F02 than F01.

TABLE 12 Round 1 Monomer Purity (%), at t0, t2 (40° C.), t4 (25° C.),and t4 (5° C.) Sample t0 t2 wk 40° C. Δ t2 40° C. t4 wk 25° C. Δ t4 25°C. t4 wk 5° C. Δ t4 5° C. F01 98.73 96.63 2.10 98.56 0.18 98.70 0.03 F0298.66 95.95 2.71 98.45 0.21 98.63 0.02 F03 98.61 94.86 3.74 98.31 0.3098.56 0.04 F04 98.36 72.78 25.58 97.80 0.56 98.30 0.06 F05 98.86 97.731.13 98.76 0.09 98.83 0.03 F06 98.59 97.45 1.14 98.29 0.30 98.56 0.03F07 97.92 95.88 2.04 97.10 0.82 97.80 0.12 F08 98.58 96.51 2.07 98.240.34 98.53 0.05 F09 98.47 96.37 2.10 98.10 0.38 98.39 0.08 F10 98.5797.55 1.02 98.30 0.27 98.54 0.03 F11 98.54 97.24 1.30 98.22 0.31 98.490.05 F12 98.45 93.89 4.55 98.02 0.42 98.41 0.04 F13 98.22 96.35 1.8797.60 0.62 98.12 0.10 F14 98.36 96.37 1.99 97.94 0.43 98.32 0.04 F1598.56 Precipitated Precipitated 97.25 1.31 98.51 0.05 F16 98.61Precipitated Precipitated 97.01 1.60 98.56 0.05

TABLE 13 Round 2 Monomer Purity (%), at t0, t2 (40° C.), t4 (25° C.),and t4 (5° C.) Sample t0 t2 wk 40° C. Δ t2 40° C. t4 wk 25° C. Δ t4 25°C. t4 wk 5° C. Δ t4 5° C. F01 98.48 91.41 7.07 98.08 0.40 98.42 0.05 F0298.43 93.74 4.69 98.05 0.37 98.31 0.12 F03 98.35 93.31 5.05 97.81 0.5498.22 0.14 F06 98.48 91.56 6.92 98.06 0.42 98.45 0.03 F09 98.10 94.713.39 97.47 0.63 97.98 0.12 F10 98.27 92.55 5.72 97.72 0.55 98.12 0.15F11 98.58 95.06 3.52 98.11 0.47 98.48 0.10 F14 98.44 95.60 2.84 97.940.49 98.30 0.14 F15 98.62 94.98 3.64 98.24 0.38 98.54 0.08 F16 98.4094.66 3.75 97.79 0.61 98.34 0.06 F17 98.45 91.90 6.55 97.78 0.67 98.300.15 F18 98.66 91.47 7.19 98.31 0.36 98.56 0.10

TABLE 14 Round 4 Monomer Purity (%), for control, agitated and F/Tsamples Sample Control Agitated Δ Agitated 5x F/T Δ 5x F/T F01 PS80-free99.10 98.89 0.21 99.05 0.05 F01 0.03% PS80 98.53 98.59 −0.06 98.58 −0.05F01 0.07% PS80 98.55 98.60 −0.06 98.47 0.07 F01 0.1% PS80 98.54 98.61−0.07 98.59 −0.05 F02 PS80-free 99.14 98.07 1.07 99.15 −0.01 F02 0.03%PS80 98.71 98.62 0.09 98.68 0.03 F02 0.07% PS80 98.63 98.61 0.03 98.590.04 F02 0.1% PS80 98.63 98.67 −0.04 98.69 −0.06

TABLE 15 Round 1% LMW, t0 and t2 (40° C.) % LMW t0 % LMW t2 wk Δ LMW0.06 0.13 0.08 0.06 0.13 0.08 0.05 0.14 0.09 0.06 0.17 0.11 0.05 0.120.07 0.05 0.09 0.04 0.05 0.10 0.04 0.05 0.12 0.07 0.06 0.16 0.10 0.060.10 0.04 0.05 0.10 0.05 0.05 0.15 0.10 0.05 0.16 0.10 0.06 0.11 0.050.06 Precipitated Precipitated 0.06 Precipitated Precipitated

TABLE 16 Round 2% LMW, t0 and t4 (25° C.) Sample % LMW t0 % LMW t4 wk ΔLMW F01 0.05 0.04 −0.01 F02 0.03 0.03 0.00 F03 0.03 0.04 0.00 F06 0.040.06 0.02 F09 0.04 0.05 0.01 F10 0.03 0.03 0.00 F11 0.03 0.05 0.02 F140.03 0.04 0.01 F15 0.03 0.04 0.01 F16 0.03 0.05 0.01 F17 0.02 0.05 0.03F18 0.03 0.04 0.00

TABLE 17 Round 2% LMW, t0 and t4 (5° C.) Sample % LMW t0 % LMW t4 wk ΔLMW F01 0.05 0.03 −0.02 F02 0.03 0.04 0.01 F03 0.03 0.04 0.01 F06 0.040.03 −0.01 F09 0.04 0.04 0.00 F10 0.03 0.04 0.01 F11 0.03 0.04 0.01 F140.03 0.04 0.00 F15 0.03 0.04 0.00 F16 0.03 0.02 −0.01 F17 0.02 0.04 0.02F18 0.03 0.04 0.01

TABLE 18 Round 1 % HMW, t0 and t2 (40° C.) Sample HMW 1 t0 HMW 1 t2 wk ΔHMW 1 HMW 2 t0 HMW 2 t2 wk Δ HMW 2 F01 0  1.25  1.25 1.21 1.99 0.78 F020  1.76  1.76 1.28 2.16 0.88 F03 0  2.63  2.63 1.34 2.37 1.03 F04 023.75 23.75 1.58 3.31 1.72 F05 0  0.50  0.50 1.09 1.65 0.56 F06 0  0.29 0.29 1.35 2.17 0.82 F07 0  0.36  0.36 2.02 3.67 1.64 F08 0  0.74  0.741.37 2.63 1.26 F09 0  0.91  0.91 1.47 2.57 1.10 F10 0  0.27  0.27 1.372.07 0.70 F11 0  0.38  0.38 1.41 2.28 0.87 F12 0  2.69  2.69 1.50 3.271.77 F13 0  0.40  0.40 1.73 3.09 1.36 F14 0  0.69  0.69 1.58 2.83 1.25F15 0 Precipitated Precipitated 1.38 Precipitated Precipitated F16 0Precipitated Precipitated 1.33 Precipitated Precipitated

TABLE 19 Round 1 % HMW, t0 and t4 (25° C.) Sample HMW 1 t0 HMW 1 t4 wk ΔHMW 1 t4 HMW 2 t0 HMW 2 t4 wk Δ HMW 2 t4 F01 0 0.005  0.005 1.21 1.380.17 F02 0 0.004  0.004 1.28 1.49 0.20 F03 0 0.006  0.006 1.34 1.62 0.28F04 0 0 0.00 1.58 2.12 0.54 F05 0 0 0.00 1.09 1.17 0.08 F06 0 0 0.001.35 1.65 0.30 F07 0 0 0.00 2.02 2.83 0.81 F08 0 0 0.00 1.37 1.70 0.33F09 0 0.020  0.020 1.47 1.82 0.35 F10 0 0.005  0.005 1.37 1.63 0.26 F110 0.002  0.002 1.41 1.72 0.31 F12 0 0 0.00 1.50 1.91 0.41 F13 0 0.006 0.006 1.73 2.33 0.60 F14 0 0 0.00 1.58 2.00 0.43 F15 0 0.59 0.59 1.382.04 0.67 F16 0 0.85 0.85 1.33 2.02 0.69

TABLE 20 Round 1 % HMW, t0 and t4 (5° C.) Sample HMW 1 t0 HMW 1 t4 wk ΔHMW 1 t4 HMW 2 t0 HMW 2 t4 wk Δ HMW 2 t4 F01 0 0 0 1.21 1.25 0.04 F02 00 0 1.28 1.32 0.04 F03 0 0 0 1.34 1.39 0.05 F04 0 0 0 1.58 1.65 0.07 F050 0 0 1.09 1.12 0.03 F06 0 0 0 1.35 1.39 0.04 F07 0 0 0 2.02 2.15 0.13F08 0 0 0 1.37 1.42 0.05 F09 0 0 0 1.47 1.56 0.09 F10 0 0 0 1.37 1.410.04 F11 0 0 0 1.41 1.46 0.04 F12 0 0 0 1.50 1.55 0.05 F13 0 0 0 1.731.82 0.10 F14 0 0 0 1.58 1.63 0.05 F15 0 0 0 1.38 1.43 0.05 F16 0 0 01.33 1.37 0.04

TABLE 21 Round 2 % HMW, t0 and t2 (40° C.) Sample HMW 1 t0 HMW 1 t2 wk ΔHMW 1 t2 HMW 2 t0 HMW 2 t2 wk Δ HMW 2 t2 F01 0 5.90 5.90 1.48 2.58 1.11F02 0 3.65 3.65 1.54 2.53 0.99 F03 0 3.59 3.59 1.61 3.00 1.39 F06 0 5.785.78 1.48 2.56 1.08 F09 0 2.02 2.02 1.87 3.19 1.32 F10 0 4.17 4.17 1.703.17 1.47 F11 0 2.18 2.18 1.39 2.66 1.27 F14 0 1.52 1.52 1.53 2.80 1.26F15 0 2.43 2.43 1.35 2.49 1.14 F16 0 2.04 2.04 1.56 3.18 1.62 F17 0 4.744.74 1.52 3.23 1.71 F18 0 6.10 6.10 1.30 2.33 1.02

TABLE 22 Round 2 % HMW, t0 and t4 (25° C.) HMW 1 t4 % HMW 2 t4 SampleHMW 1 t0 wk Δ HMW 1 t4 % HMW 2 t0 wk Δ HMW 2 t4 F01 0 0 0 1.48 1.88 0.41F02 0 0 0 1.54 1.92 0.37 F03 0 0 0 1.61 2.15 0.54 F06 0 0 0 1.48 1.880.40 F09 0 0 0 1.87 2.49 0.62 F10 0 0 0 1.70 2.25 0.55 F11 0 0 0 1.391.84 0.45 F14 0 0 0 1.53 2.02 0.49 F15 0 0 0 1.35 1.72 0.38 F16 0 0 01.56 2.16 0.60 F17 0 0 0 1.52 2.17 0.64 F18 0 0 0 1.30 1.66 0.35

TABLE 23 Round 2 % HMW, t0 and t4 (5° C.) Sam- HMW HMW % HMW t4 ple 1 t01 t4 wk Δ HMW 1 t4 % HMW t0 wk Δ HMW F01 0 0 0 1.48 1.55 0.07 F02 0 0 01.54 1.65 0.11 F03 0 0 0 1.61 1.74 0.13 F06 0 0 0 1.48 1.53 0.04 F09 0 00 1.87 1.98 0.11 F10 0 0 0 1.70 1.84 0.14 F11 0 0 0 1.39 1.49 0.10 F14 00 0 1.53 1.67 0.13 F15 0 0 0 1.35 1.42 0.08 F16 0 0 0 1.56 1.63 0.07 F170 0 0 1.52 1.66 0.14 F18 0 0 0 1.30 1.40 0.09

TABLE 24 Round 4% HMW 1 for control, agitated and F/T Samples HMW1 HMW1HMW1 HMW1 HMW1 Sample Control Agitated Δ Agitated 5x F/T Δ 5x F/T F01PS80-free 0.11 0.19 0.07 0.12 0.01 F01 0.03% PS80 0 0 0 0 0 F01 0.07%PS80 0 0 0 0 0 F01 0.1% PS80 0 0 0 0 0 F02 PS80-free 0.14 0.65 0.51 0.12−0.02 F02 0.03% PS80 0 0 0 0 0 F02 0.07% PS80 0 0 0 0 0 F02 0.1% PS80 00 0 0 0

TABLE 25 Round 4% HMW 2 for Control, Agitated and F/T Samples HMW2 HMW2HMW2 HMW2 HMW2 Sample Control Agitated Δ Agitated 5x F/T Δ 5x F/T F01PS80-free 0.75 0.89 0.15 0.80 0.05 F01 0.03% PS80 1.45 1.40 −0.05 1.41−0.04 F01 0.07% PS80 1.44 1.39 −0.05 1.51 0.07 F01 0.1% PS80 1.44 1.38−0.06 1.14 −0.04 F02 PS80-free 0.69 1.24 0.55 0.70 0.01 F02 0.03% PS801.28 1.36 0.08 1.31 0.03 F02 0.07% PS80 1.35 1.37 0.02 1.39 0.05 F020.1% PS80 1.35 1.32 −0.03 1.31 −0.05

A partial least squares regression was performed to model monomercontent at t2 (samples after two weeks at 40° C.). FIG. 4 shows anexemplary graph depicting predicted vs. measured monomer content.

In Round 1 experiments, the data indicated that formulation 4 may not berepresentative. The data indicate that histidine appears to bestabilizing in this model, while citrate and phosphate showed littleability to maintain monomer content. Additionally, while arginineappears to destabilize the protein at a higher storage temperature (40°C.), it was protective or stabilizing at lower storage temperatures (25°C. or lower). Sorbitol was seen to have little effect on the stabilityof the antibody. NaCl appeared to be the best stabilizer of thosetested. Storage stability appeared to be constant up to a proteinconcentration of approximately 100 mg/mL, but it decreased above thatconcentration. Indeed, similar to Round 1, the SEC data from Round 2indicates that the propensity of the antibody to aggregate increaseswith higher concentrations of the antibody, as the amount of HMWcomponents formed for these Round 2 formulations (200 mg/mL) is greaterthan those measured for comparable, lower protein concentrationformulations from Round 1.

Charge Distribution

The purity of the main charge variant (main peak) for the samples fromRound 1 and Round 2 was determined by capillary isoelectric focusing(cIEF). cIEF was conducted using the Beckman Coulter kit method on a PA800 Plus instrument. cIEF data from Round 1 of the percentage of themain peak at t0, after two weeks at 40° C. (t2) and after four weeks at25° C. (t4) are shown below in Table 26. cIEF data from Round 2 of thepercentage of the main peak at t0, after two weeks at 40° C. (t2) andafter four weeks at 25° C. (t4) are shown below in Table 27.

In general, loss of the main isoform was correlated with the pH of theformulations. Higher pH formulations had a greater loss of main isoformat both t2/40° C. and t4/25° C., with the loss mainly manifesting itselfas an increase in acidic charge forms. An exception in Round 1 was F04(pH 6.0) at t2, which showed a loss of main peak to both acidic andbasic sides of the main peak.

TABLE 26 Round 1 % main peak, t0, t2 and t4 % Main Peak % Main Peak Sam-t2 wk t4 wk ple Buffer pH t0 40° C. Δ t2 t0 25° C. Δ t4 F01 citrate 6.6051.2 43.5  7.7 51.2 51.0 0.2 F02 citrate 6.59 50.9 43.5  7.4 50.9 50.70.2 F03 citrate 6.57 50.6 42.7  7.9 50.6 49.9 0.7 F04 succinate 6.0149.0 36.8 12.2 49.0 48.8 0.2 F05 His 6.57 48.5 41.6  6.9 48.5 49.4 −0.9F06 His 6.89 49.6 40.7  8.9 49.6 48.3 1.3 F07 phos 7.17 50.5 33.1 17.450.5 46.2 4.3 F08 His 6.60 50.5 41.8  8.7 50.5 51.0 −0.5 F09 His 7.5050.1 34.5 15.6 50.1 46.1 4.0 F10 His 7.19 50.3 40.3 10.0 50.3 49.5 0.8F11 phos 6.54 51.2 42.2  9.0 51.2 51.5 −0.3 F12 phos 6.09 51.4 41.4 10.051.4 51.5 −0.1 F13 phos 7.47 49.9 28.0 21.9 49.9 45.5 4.4 F14 succinate6.56 51.0 43.4  7.6 51.0 51.8 −0.8 F15 citrate 5.48 50.5 Precip- Precip-50.5 49.0 1.5 itate itate F16 succinate 5.39 52.0 Precip- Precip- 51.748.0 3.7 itate itate

TABLE 27 Round 2 % main peak, t0, t2 and t4 % Main Peak % Main Peak t4wk Sample pH t0 t2 wk 40° C. Δ t2 t0 25° C. Δ t4 F01 6.57 51.1 42.4  8.751.1 50.6 0.5 F02 6.75 50.8 44.4  6.4 50.8 48.8 2.0 F03 6.58 50.9 42.6 8.3 50.9 49.6 1.3 F06 6.56 50.7 44.2  6.5 50.7 50.1 0.6 F09 6.84 50.545.2  5.3 50.5 49.4 1.1 F10 6.59 51.1 45.0  6.1 51.1 49.2 1.9 F11 6.6850.3 44.4  5.9 50.3 49.2 1.1 F14 6.97 49.8 39.1 10.7 49.8 47.0 2.8 F156.66 50.3 43.9  6.4 50.3 49.0 1.3 F16 6.60 49.6 43.7  5.9 49.6 48.7 0.9F17 6.57 49.4 42.1  7.3 49.4 48.7 0.7 F18 6.58 50.4 44.3  6.1 50.4 48.81.6

A partial least squares regression was performed to model cIEFdifference in main peak percentage data from Round 1 at both t2 (samplesafter two weeks at 40° C.) and t4 (samples after four weeks at 25° C.).The model for t2 only used data from formulations 1-13. A partialleast-squares (PLS) model generated from the t2/40° C. data demonstratedthe stabilization afforded by NaCl compared to an excipient likemannitol. FIG. 5 shows an exemplary graph depicting predicted vs.measured cIEF difference in main peak percentage at t2. FIG. 6 shows anexemplary graph depicting predicted vs. measured cIEF difference in mainpeak percentage at t4. The correlation coefficients for the variousformulation variables at t2 and t4 are shown in FIG. 7.

Susceptibility to Interfacial Damage

Samples from Round 4 were tested to determine the susceptibility of theanti-OSMR antibody (formulated with varying levels of PS80) tointerfacial damage when exposed to freeze-thaw (F/T) and agitationstresses. F/T studies were conducted by freezing samples at −80° C. for≥17 hours followed by thawing at room temperature for approximately 4hours. Samples were mixed (by swirling) between freeze thaw cycles. Atotal of 5 F/T cycles were performed. Agitation was conducted by shakingat 590 rpm (on an orbital shaker, 3 mm orbit) for 24 hours at 25° C. Forboth the F/T and agitation studies, the container/closure consisted of a1 mL Type 1 glass vial with Fluorotec stopper. The fill volume was 400μL and the vial orientation was vertical and horizontal for the F/T andagitation study, respectively.

Two formulations were chosen to conduct this study (based upon theirviscosity and stability profiles), and their compositions are listedabove in Table 4. The measured PS80 content for each sample is givenbelow in Table 28. The results of these analyses are summarized below.PS80 content for each formulation was determined using a PS80 assayconsisting of free oleic acid determination using RP-HPLC to indirectlydetermine PS80 content. Free oleic acid was obtained by hydrolyzing thePS80 contained within a given formulation. This free oleic acid was thenanalyzed via Reversed-Phase High-Performance Liquid Chromatography(RP-HPLC) and concentration was determined against a standard curvegenerated with PS80 standards (hydrolyzed to obtained free oleic acid)prepared from the same PS80 (here JT Baker) used to prepare a givenformulation. The standard curve consisted of 5 PS80 concentrationsranging from 0.0005-0.005% (w/v) PS80.

TABLE 28 Round 4 Measured PS80 Content Measured PS80 Content (% Samplew/v) F01 PS 80-free N/A F01 0.03% PS80 0.027 F01 0.07% PS80 0.068 F010.1% PS80 0.095 F02 PS 80-free N/A F02 0.03% PS80 0.027 F02 0.07% PS800.065 F02 0.1% PS80 0.091

Protein content obtained from UV-absorbance at 280 nm (A280) for theagitation and F/T samples is shown below in Table 29. Protein contentfor all samples was unchanged (within the error of the measurement)compared to the starting material (pre-PS80 material), indicating thatsignificant amounts of precipitation that would be capable of changingprotein concentration did not occur for these samples.

TABLE 29 Round 4 protein content (mg/mL) Starting Agitated SampleMaterial (mg/mL) (mg/mL) 5x F/T F01 PS80-free 191.42 191.60 190.01 F010.03% PS80 188.23 194.10 193.26 F01 0.07% PS80 188.23 194.71 192.81 F010.1% PS80 188.23 194.01 191.14 F02 PS80-free 186.73 188.29 186.76 F020.03% PS80 195.24 201.25 195.72 F02 0.07% PS80 195.24 204.66 198.88 F020.1% PS80 195.24 198.01 194.62

Round 4 studies, including additional sub-visible particle (SVP) anddynamic light scattering (DLS) analyses (data not shown) indicated thatthe anti-OSMR antibody was, under certain conditions, prone to particleformation in the absence of PS80. In particular, the molecule appears tobe most prone to particle formation during agitation processes. Insamples lacking PS80, the SEC results show that F01, which containsNaCl, was able to suppress the formation of impurities to a greaterextent than F02, which lacks NaCl. Inclusion of PS80 at just 0.03% (w/v)was shown to be sufficient in protecting against the formation ofaggregates. F01 and F02 formulations with PS80 at 0.03%, 0.07% and 0.1%(w/v) were shown by SEC and SVP to protect against aggregate formationto a similar extent. Additionally, upon agitation, the F01 formulationsappeared to be less prone to SVP formation (total particle counts)compared to F02 formulations.

Example 5: Drug Substance Stability Over Extended Period at DifferentIncubation Temperatures

This example illustrates that the anti-OSRMβ antibody in formulationbuffer (20 mM L-histidine, 25 mM L-arginine hydrochloride, 125 mM sodiumchloride, 0.05% (w/v) polysorbate 80, pH 6.6) is stable at temperatureof −70° C. or 5° C., at least to 3 months. Samples were pulled fromstorage at different temperatures and the various characteristics wereexamined. FIG. 8 illustrates observed characteristics of two exemplarysamples pulled for examination at indicated time periods from thestorage temperature of −70° C. and 5° C. relative to the baseline(time=0). FIG. 9 illustrates observed characteristics of two exemplarysamples pulled at indicated time periods from the storage temperature of25° C. (accelerated), and 40° C. (stressed conditions) relative to thebaseline. Size exclusion chromatography (SEC) results over the period ofthree months at different temperatures of storage, −70° C. and 5° C.,(FIG. 8) as well as at accelerated conditions by storage at 25° C. (FIG.9) indicate the relative amount of aggregates were repeatedly less than5% for as long as 3 months. Additionally, the formulation samples wereanalyzed by non-reducing capillary gel electrophoresis (CE-SDS (NR))over a period of three months at the indicated times to detect intactIgG monomers and fragments of IgG as a measure of stability of theformulation. Non-reducing SDS data in the figures indicate greater than90% of the antibody (drug substance) existed as intact monomers atstorage temperatures of −70° C. and 5° C., (FIG. 8) as well as ataccelerated conditions by storage at 25° C. for the period of 3 months.With storage at 40° C. (FIG. 9), however, samples showed higherpercentage of aggregates and lower percent of intact IgG monomers.

Example 6: Drug Substance Production Stress—Robustness Analysis

In this exemplary study, a freeze/thaw profile was generated using aplacebo (20 mM L-Histidine, 25 mM L-Arginine-HCl, 125 mM NaCl, 0.05%PS80, pH 6.6) within a Sartorius Celsius Flexible Freeze and Thaw (FFT)container. Based on the freeze/thaw profile, the drug substance informulation buffer (20 mM L-histidine, 25 mM L-arginine hydrochloride,125 mM sodium chloride, 0.05% (w/v) polysorbate 80, pH 6.6-6.8) wassubjected to repeated freeze/thaw cycles and placed at 25° C. in orderto assess the robustness of the formulation following stress conditionsrelevant in drug substance production.

During this drug substance production stress study, the drug substancewas stressed by being subjected to three (3) consecutive freeze/thawcycles, followed by three (3) months incubation at 25° C. An additionalsample (Control) of the formulation remained at 2-8° C. to serve as anunstressed control.

After being stressed by three (3) cycles of controlled freezing andthawing, the API in the current formulation did not exhibit significantdifferences from an unstressed Control by visual appearance, pH, APIconcentration, SE-UPLC, IE-HPLC, or MFI.

After 3 months of incubation at 25° C., no differences in visualappearance, pH, or API concentration were noted between the stressedsamples and the control samples. Slight physical degradation wasobserved by SE-UPLC, which was orthogonally supported by CE-SDS. Thestressed sample exhibited increases in sub-visible particle countscompared to the control by MFI. Slight chemical modification wasobserved by IE-HPLC. These degradations are likely due to thermal stressand not the result of the Freeze-Thaw cycling. Main degradants wereidentified as aggregate species by SE-UPLC and acidic species byIE-HPLC.

Example 7: In-Use Compatibility of Drug Product

In this exemplary study, 1 mL of the drug product was drawn intodisposable 3-cc and 1-cc sterile syringes via a 21G 1½″ needle. Thefilled syringes were then incubated with the needle attached at 25°C.±2° C. and 5±3° C. stability chambers and analyzed at six (6) timepoints: 0, 1, 4, 8, 16 and 24 hours. At each time point, the drug wasexpelled from the syringes through a 27G ½″ needle into a sterile 2 ccvial. Expelled samples were analyzed immediately by visual appearance,concentration, SEC, and MFI. All samples were free of visible particles.The visual observations remained unchanged by the temperature storageconditions or storage duration. Regardless of syringe size or incubationtemperature, the API concentration for all samples remained at or near(Δ≤2.3%) the target concentration.

Also, regardless of syringe size, no significant changes inchromatographic profiles or peak percentages were detected following 24hours of incubation at either 5° C. or 25° C., in comparison to timezero values. Results were comparable to time zero values as well to theunstressed control samples.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. The scope of the presentinvention is not intended to be limited to the above Description, butrather is as set forth in the following claims:

1. A stable formulation comprising an anti-oncostatin M receptor (OSMR)antibody and having a pH ranging from approximately 6.0-7.6, whereinless than approximately 5% of the anti-OSMR antibody exists as highmolecular weight (HMW) species in the formulation.
 2. The stableformulation of claim 1, wherein less than 5%, 4%, 3%, 2%, 1%, or 0.5% ofthe anti-OSMR antibody exists as HMW species in the formulation. 3-12.(canceled)
 13. The stable formulation of claim 1, wherein the pH of theformulation is approximately 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.27.4 or 7.6.
 14. The stable formulation of claim 1, wherein the anti-OSMRantibody is present at a concentration of at least approximately 50mg/mL. 15-16. (canceled)
 17. The stable formulation of claim 1, whereinthe anti-OSMR antibody has a pI ranging from 6.5-8.5. 18-53. (canceled)54. A stable, injectable formulation of an anti-oncostatin M receptor(OSMR) antibody, comprising: 50-250 mg/mL of the anti-OSMR monoclonalantibody, 10-150 mM arginine, 10-150 mM histidine, 25-150 mM sodiumchloride (NaCl), 0.05%-0.5% (w/v) polysorbate 80 (PS80), pH range6.0-7.6, wherein the formulation is an isotonic solution, and wherein atleast 90% of the antibody exists as stable intact monomeric IgG at about−70° C. or at about 5° C. temperature for at least 1 month. 55-61.(canceled)
 62. The stable formulation of claim 54, wherein the anti-OSMRantibody is present at a concentration of approximately 200 mg/mL.63-105. (canceled)
 106. A method of treating a disease, disorder orcondition associated with OSMR comprising administering into a subjectin need of treatment a stable formulation of claim
 1. 107. The method ofclaim 106, wherein the formulation is administered intravenously. 108.The method of claim 106, wherein the formulation is administeredsubcutaneously. 109-115. (canceled)
 116. The method of claim 106,wherein the anti-OSMR antibody comprises: a light chaincomplementary-determining region 1 (LCDR1) defined by SEQ ID NO: 8, alight chain complementary-determining region 2 (LCDR2) defined by SEQ IDNO: 9, and a light chain complementary-determining region 3 (LCDR3)defined by SEQ ID NO: 10; and a heavy chain complementary-determiningregion 1 (HCDR1) defined by SEQ ID NO: 5, a heavy chaincomplementary-determining region 2 (HCDR2) defined by SEQ ID NO: 6, anda heavy chain complementary-determining region 3 (HCDR3) defined by SEQID NO:
 7. 117-121. (canceled)
 122. The method of claim 106, wherein theformulation is administered in a volume of less than 5 mL, 4 mL, 3 mL,or 2 mL. 123-125. (canceled)
 126. The method of claim 106, wherein lessthan 5%, 4%, 3%, 2%, 1%, or 0.5% of the anti-OSMR antibody exists as HMWspecies in the formulation.
 127. The method of claim 106, wherein therelative amount of HMW species in the formulation increases less than5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25° C. for more than 2weeks. 128-131. (canceled)
 132. The formulation of claim 54, wherein theformulation is stable at 25° C. following 1, 2 or 3 freeze/thaw cyclesfor at least three months.
 133. The formulation of claim 54 whereinstorage of the formulation at −70° C. for about at least 3 monthsresults in the formulation comprising less than about 5% aggregates, andgreater than at least 90% intact antibody IgG monomer.
 134. Theformulation of claim 54 wherein storage of the formulation at 5-8° C.for about at least 3 months results in the formulation comprising lessthan about 5% aggregates, and greater than about 90% intact antibody.135. The formulation of claim 54 wherein storage of the formulation at25° C. results in the formulation comprising less than 5% aggregates,greater than 90% intact antibody for up to at least 1 month.
 136. Theformulation of claim 54 wherein storage of the formulation at 25° C.results in the formulation comprising less than 5% aggregates, greaterthan 90% intact antibody for up to at least 3 months.